You are on page 1of 11

REVIEW ARTICLE

Pharmacokinetics and Pharmacodynamics in Clinical


Use of Scopolamine
Ulf D. Renner, Reinhard Oertel, and Wilhelm Kirch

Although scopolamine has been used in clinical practice for many


Abstract: The alkaloid L-(2)-scopolamine [L-(2)-hyoscine] com- years, data concerning its metabolism and the renal excretion in man are
petitively inhibits muscarinic receptors for acetylcholine and acts as limited. After incubation with b-glucuronidase and sulfatase, the
a nonselective muscarinic antagonist, producing both peripheral anti- recovery of scopolamine in human urine increased from 3% to
muscarinic properties and central sedative, antiemetic, and amnestic approximately 30% of the drug dose (intravenously administered).
effects. The parasympatholytic scopolamine, structurally very similar According to these results from enzymatic hydrolysis of scopolamine
to atropine (racemate of hyoscyamine), is used in conditions requiring metabolites, the glucuronide conjugation of scopolamine could be
decreased parasympathetic activity, primarily for its effect on the eye, the relevant pathway in healthy volunteers. However, scopolamine
gastrointestinal tract, heart, and salivary and bronchial secretion glands, metabolism in man has not been verified stringently. An elucidation of
and in special circumstances for a CNS action. Therefore, scopolamine the chemical structures of the metabolites extracted from human urine is
is most suitable for premedication before anesthesia and for antie- still lacking.
metic effects. This alkaloid is the most effective single agent to prevent Scopolamine has been shown to undergo an oxidative demethylation
motion sickness. Scopolamine was the first drug to be made commer- during incubation with CYP3A (cytochrome P-450 subfamily). To
cially available in a transdermal therapeutic system (TTS-patch) de- inhibit the CYP3A located in the intestinal mucosa, components of
livering alkaloid. Recently, pharmacokinetic data on scopolamine in grapefruit juice are very suitable. When scopolamine was administered
different biozlogic matrices were obtained most efficiently using liq- together with 150 mL grapefruit juice, the alkaloid concentrations con-
uid chromatographictandem mass spectrometric (LC-MS/MS) or tinued to increase, resulting in an evident prolongation of tmax (59.5 6
gas chromatography online coupled to mass spectrometry. 25.0 minutes; P , 0.001). The AUC024h values of scopolamine were
Pharmacokinetic parameters are dependent on the dosage form higher during the grapefruit juice period. They reached approximately
(oral dose, tablets; parenteral application; IV infusion; SC and IM in- 142% of the values associated with the control group (P , 0.005).
jection). Scopolamine has a limited bioavailability if orally admin- Consequently, the related absolute bioavailabilities (range 6% to 37%)
istered. The maximum drug concentration occurs approximately were significantly higher than the corresponding values of the drug orally
0.5 hours after oral administration. Because only 2.6% of nonmet- administered together with water (range 3% to 27%).
abolized L-(2)-scopolamine is excreted in urine, a first-pass metab- The effect of the alkaloid on quantitative electroencephalogram
olism is suggested to occur after oral administration of scopolamine. (qEEG) and cognitive performance correlated with pharmacokinetics was
Because of its short half-life in plasma and dose-dependent adverse shown in studies with healthy volunteers. From pharmacokinetic
effects (in particular hallucinations and the less serious reactions, eg, pharmacodynamic modeling techniques, a direct correlation between
vertigo, dry mouth, drowsiness), the clinical use of scopolamine serum concentrations of scopolamine and changes in total power in
administered orally or parenterally is limited. To minimize the relatively a-frequency band (EEG) in healthy volunteers was provided.
high incidence of side effects, the transdermal dosage form has been The alkaloid readily crosses the placenta. Therefore, scopolamine
developed. The commercially available TTS-patch contains a 1.5-mg should be administered to pregnant women only under observation. The
drug reservoir and a priming dose (140 mg) to reach the steady-state drug is compatible with nursing and is considered to be nonteratogenic.
concentration of scopolamine quickly. The patch releases 0.5 mg In conclusion, scopolamine is used for premedication in anesthesia
alkaloid over a period of 3 days (releasing rate 5 mg/h). Following the and for the prevention of nausea and vomiting associated with motion
transdermal application of scopolamine, the plasma concentrations of sickness. Pharmacokinetics and pharmacodynamics of scopolamine
the drug indicate major interindividual variations. Peak plasma depend on the dosage form. Effects on different cognitive functions have
concentrations (Cmax) of approximately 100 pg/mL (range 11240 pg/ been extensively documented.
mL) of the alkaloid are reached after about 8 hours and achieve steady
Key Words: scopolamine, pharmacokinetics, pharmacodynamics
state. During a period of 72 hours the plaster releases scopolamine, so
constantly high plasma levels (concentration range 56245 pg/mL) are (Ther Drug Monit 2005;27:655665)
obtained, followed by a plateau of urinary scopolamine excretion.

Received for publication November 1, 2004; accepted March 1, 2005. CHEMISTRY AND DOSAGE FORMS
From the Institute of Clinical Pharmacology, Medical Faculty Carl Gustav OF SCOPOLAMINE

T
Carus, Technical University of Dresden, Dresden, Germany. he parasympathicolytic drugs constitute a large class of
Reprints: Dr. Reinhard Oertel, Institute of Clinical Pharmacology, Medical
Faculty Carl Gustav Carus, Technical University of Dresden, Fiedlerstrasse
anticholinergic agents and can be divided into 2 sub-
27, D-01307 Dresden, Germany (e-mail: reioer@rcs.urz.tu-dresden.de). classes: (1) natural parasympathicolytics (eg, scopolamine,
Copyright 2005 by Lippincott Williams & Wilkins atropine) and (2) (semi)synthetic parasympathicolytic agents.

Ther Drug Monit  Volume 27, Number 5, October 2005 655


Renner et al Ther Drug Monit  Volume 27, Number 5, October 2005

The latter subclass consists of quaternary ammonium com- Scopolamine is available in infusion solutions with 0.3,
pounds with ganglioplegic effects (eg, N-butyl-scopolamine) 0.5, or 1.0 mg/mL scopolamine hydrobromide3H2O in a
and substances with additional myogenous spasmolytic transdermal patch containing a reservoir of 1.5 mg scopol-
properties (eg, denaverine). The quaternary ammonium moiety amine (mean release 1.0 mg/72 hours) and in eye drops with
in synthetic parasympatholytic drugs minimize the side effects 2.1 mg scopolamine borate dissolved in 1 g solution. A nasal
on the central nervous system (CNS) because the polar administration of scopolamine was tested using an aerosol
structures decrease their lipid solubility and prevent crossing spray releasing 0.1% or 0.2% scopolamine hydrobromide.3,4
the bloodcerebrospinal fluid barrier.
L-(2)-Scopolamine (synonym: L-(2)-hyoscine) is found
in various Solanaceae, eg, Scopola carniolica, Hyoscyamus ANALYTIC METHODS
niger, and Datura stramonium. The structure of the tertiary First data1,59 about pharmacokinetics (PK) of scopol-
amine L-(2)-scopolamine (tropic acid ester with scopine; amine were obtained using a stereospecific enzyme immuno-
MW = 303.4; Fig. 1) is very similar to that of atropine assay [sensitivity to L-(2)-hyoscine, 20 ng/L] or a radio-
[(6)-hyoscyamine = racemate of hyoscyamine]. receptor assay (RRA) for the hyoscine racemate based on the
The structures of both substances have 1 asymmetric competition between the alkaloid and a radiolabeled ligand for
carbon atom (chiral center) localized in the tropic acid com- binding to a certain receptor.
ponent [S-(2)-tropate]. Derived from the tropine substructure To remove compounds interfering with scopolamine
in the atropine compound, the scopine moiety differs only in an detection by a radioreceptor assay, high-performance liquid
epoxy function, bridged over the C-C bond (position C-6b and chromatography (HPLC) was used to separate the analyte.3
C-7b) of the 1aH,5aH-tropan-3a-ol (tropine). Several HPLC methods were developed for the analysis of
Scopolamine has a weak basic character (pKa = 7.6) and scopolamine in biologic matrices (eg, plasma, urine, plants).1012
a good lipid solubility expressed by a partition coefficient of Capillary zone electrophoresis (CZE) coupled to UV
1.2 (n-octanol:buffer pH 7.4). detection and interfaced with electrospray ionization (ESI)
The drug reacts as a nonselective muscarinic antagonist mass spectrometry is described for the analysis of scopolamine
with both peripheral antimuscarinic properties and central in plants.13
sedative, antiemetic, and amnestic effects.1 In recent years both liquid chromatographytandem
The atropine-like drugs are used in conditions requiring mass spectrometry (LC-MS/MS)10,14 and gas chromatography
decreased parasympathetic activity, primarily for their effect online coupled to mass spectrometry (GC-MS) have been used
on the eye, gastrointestinal tract, heart, secretions, and in to determine concentrations of scopolamine in different bio-
special circumstances for a CNS action. Scopolamine is more logic matrices (eg, plasma, serum).1520
potent than atropine on the eye, salivary and bronchial secre- For GC-MS/MS methods for generating pharmacoki-
tion glands, and on CNS. Therefore, this drug is most suitable netic data on scopolamine in 1 mL serum19 or 4 mL plasma,16
for use for preoperative sedation as an injection and for its respectively, extensive sample preparation consisted of
antiemetic effect as subcutaneous dosage. a liquidliquid extraction, and a precolumn derivatization is
Scopolamine was the first drug to be made commercially necessary to achieve a sensitivity of 50 ng/L.
available as a transdermal therapeutic system (TTS) delivering The liquid chromatographytandem mass spectrometry
drug (Scopoderm TTS patches, Novartis).2 Because the (LC-MS/MS) with an automated solid-phase extraction (SPE)
postauricular area is the most permeable skin site, a trans- sample preparation is the most qualified method to determine
dermal scopolamine patch is placed on a hairless area behind scopolamine in serum samples of patients, requiring smaller
the ear for motion sickness and prevention of postoperative serum volumes and enabling a lower limit of quantification.
nausea and vomiting. The chromatographic separation is performed on a
For refraction, ophthalmic scopolamine (1 or 2 drops) is RP18e column with a mobile phase gradient. High sensitivity
applied topically to the eye 1 hour before refraction; for uveitis, is provided by detecting both mass transitions between m/z 304
1 or 2 drops are applied up to 4 times daily. and m/z 138 and between m/z 304 and m/z 156 in the tandem

FIGURE 1. Structure of L-(2)-scopolamine (L-(2)-hyoscine), atropine (hyoscyamine), and N-butyl-L-(2)-scopolamine; * =


chiral center.

656 q 2005 Lippincott Williams & Wilkins


Ther Drug Monit  Volume 27, Number 5, October 2005 Scopolamine Pharmacokinetics

mass spectrometer. The limit of quantification of scopolamine,


ie, a coefficient of variation ,20% for 6 repeated measure-
ments, is 20 ng/L.10

PHARMACOKINETICS
Administration and Plasma Concentrations
The pharmacokinetic parameters depend on the dosage
form (Table 1). The oral dose (tablets), parenteral injection
(intravenous, subcutaneous, or intramuscular), and the trans-
dermal form are different administration modes well established FIGURE 2. Area under scopolamine concentration in serum
for scopolamine. versustime (AUC) curve following intravenous infusion of
Following oral administration the bioavailability of 
0.5 mg scopolamine in 7 healthy male ( ) and 7 healthy
female volunteers (s). The solid bar represents infusion dura-
scopolamine is limited. The pharmacokinetic profile com-
tion. From Ebert et al15 with permission.
prises levels returning close to baseline 5 to 6 hours after dose.
The pharmacokinetics of 0.5 mg scopolamine orally admin-
istered together with 150 mL water to female and male healthy
volunteers were (geometric mean 6 geometric SD) tmax = 23.5 6 were Cmax = 0.96 6 0.17 ng/mL (mean of 10 individual
8.2 minutes, Cmax = 0.54 6 0.10 ng/mL, t = 63.7 6 1.3 maximum drug concentrations 6 SD), tmax = 18.5 6 4.7
minutes, AUC024h = 50.77 6 1.76 ngmin/mL, and F = 13 6 minutes (mean 6 SD), AUC06h = 81.27 6 11.21 ngmin/mL
1% (F = AUCoral/AUCIV; absolute bioavailability).15 (mean 6 SD), tlag = 3.4 6 1.40 minutes (lag time after
The pharmacokinetic parameters of scopolamine (after IM injection; mean 6 SD), and tb = 69.1 6 8.00 minutes
IV infusion of 0.5 mg over period of 15 minutes) were shown (mean 6 SD).20
to be as follows (geometric mean 6 geometric SD): CL = Because of its short half-life in plasma and dose-
81.2 6 1.55 L/h, Vd = 141.3 6 1.6 l, t = 68.7 6 1.0 minutes, dependent adverse effects (in particular hallucinations and the
Cmax = 5.00 6 0.43 ng/mL, and AUC024h = 369.4 6 2.2 less serious reactions, eg, vertigo, dry mouth, drowsiness), the
ngmin/mL (Fig. 2). The Cmax value in the male subjects was clinical use of scopolamine administered orally or parenterally
significantly higher compared with the value in the female (bolus therapy) is limited. An intravenous infusion study
subjects (6.61 6 0.63 ng/mL vs 3.93 6 0.04 ng/mL; P = established the relationship between adverse effects of the
0.007). Relating to the other parameters, there were no dif- drug and the increasing urinary excretion of scopolamine.21,22
ferences in sex. The pharmacokinetic parameters obtained To minimize the relatively high incidence of side effects,
after oral and intravenous administration were calculated the transdermal dosage form was developed. The transdermal
according to a noncompartment model.15 delivery system for scopolamine was introduced in 1981. The
After subcutaneous administration of 0.4, 0.6, or 0.8 mg commercially available small round TTS-patch (4 layers;
scopolamine to male healthy volunteers, Cmax increased from thickness 0.2 mm; size 2.5 cm2) contains a 1.5-mg drug
3.27 ng/mL to 18.81 ng/mL, and AUC08h from 158.2 to 455.6 reservoir and a priming dose (140 mg) to bring plasma con-
ngmin/mL, dependent on dose. In contrast, tmax ranged centrations of scopolamine to steady state. The patch releases
between 11.4 and 17.8 minutes, t between 3.3 and 3.8 hours, 0.5 mg alkaloid over a period of 3 days (releasing rate 5 mg/h).
and CL between 0.14 and 0.17 L/h independent of the alkaloid Relative to the release and skin permeation of scopol-
dose. A large interindividual variation of the serum concen- amine in vitro, the urinary drug excretion in vivo approaches
trations of scopolamine was found.17 a 0.1-fold rate of the alkaloid release in vitro approximately 4
Scopolamine is rapidly absorbed from muscle, eg, hours after application of the TTS patch, assuming a recovery
deltoid muscle. Following intramuscular injection of scopol- of only 10% unchanged drug in urine. Thus, scopolamine is
amine (0.5 mg), the corresponding pharmacokinetic values constantly excreted in urine over a period of many hours.23,24

TABLE 1. The Most Important Pharmaco Kinetic Data


Application IV Oral SC IM IN
Dose (mg) 0.5 0.5 0.4 0.5 0.4
Cmax (ng/mL) 5.00 6 0.43 0.54 6 0.10 3.27 0.96 6 0.17 1.68 6 0.23
tmax (min) 5.0 23.5 6 8.2 14.6 18.5 6 4.7 2.2 6 3
AUC
(ng*min/mL) 369.4 6 2.2 50.8 6 1.76 158.2 81.3 6 11.2 167 6 20
t1/2 (min) 68.7 6 1.0 63.7 6 1.3 213 69.1 6 8.0 ND
F (%) 100 13 6 1 ND ND 83 6 10
ND, no data.

q 2005 Lippincott Williams & Wilkins 657


Renner et al Ther Drug Monit  Volume 27, Number 5, October 2005

Following the transdermal application of a scopolamine Scopolamine is a relatively nonpolar, tertiary amino
via TTS-patch, the plasma scopolamine concentrations com- compound and should be well absorbed from the gastroin-
bined with the urinary excretion of the drug were analyzed in testinal tract. However, one of the pharmacological effects of
patients and children.2540 The plasma concentrations of the this drug is the suppression of intestinal motility and gastric
drug indicated major interindividual variations. Peak plasma secretion. Both effects may influence the absorption after oral
concentrations (Cmax) of approximately 100 pg/mL (range 11 administration and limit oral bioavailability of scopol-
240 pg/mL) of the alkaloid were achieved after about 8 hours amine.42 Only 2.6% of the drug is excreted in urine in
and reached steady state. Over a period of 72 hours the plaster a pharmacologically active form.43 Based on this fact, a first-
was releasing scopolamine, constant high plasma levels (range pass metabolism is suggested to occur after oral administra-
of the peak values: 56245 pg/mL) were obtained, followed by tion of scopolamine.
a plateau of urinary scopolamine excretion. Concerning the limited data about metabolism of
For comparison to the oral and IV administration, the scopolamine in man and, on the other hand, the potential
bioavailability of scopolamine intranasally (IN) administered variety of scopolamine metabolites, the metabolic pathways of
was analyzed in healthy nonsmoking male volunteers.3 The scopolamine analyzed in animal studies are to be described
subjects received a 0.4-mg dose of scopolamine hydrobromide more in detail.
intranasally on 3 occasions, with at least 2 weeks separating In studies with scopolamine administered subcutane-
the doses. The absorption after IN drug application was rapid, ously and intraperitoneally, respectively, different metabolites
and the pharmacokinetic parameters (mean 6 SD) were Cmax = were identified chemically in the urine of several mam-
1.68 6 0.23 ng/mL, tmax = 22.2 6 3 minutes, AUC024h = mals.44,45 Total unchanged scopolamine and the metabolites
166.8 6 19.8 ngmin/mL, and FIN = 83 6 10%. The absolute excreted in 24-hour urine of mammals varies in diverse animal
bioavailability FIN was found to significantly greater than that species both qualitatively and quantitatively (range 29% to
of FPO (P , 0.05). Time to reach maximum effect was 1.05 .80% of the administered dose). Various metabolic pathways
hours after IN dosage.3 are shown in Figure 5. Following the administration and
After ocular administration, scopolamine is rapidly, metabolism of L-(2)-[9-14C]scopolamine, the radioactivity of
efficiently, and systemically absorbed. The systemic absorp- the N-methyl group of the scopine component was expired
tion of the alkaloid eye drops (40 mL 0.25% scopolamine as 14CO2 by mammals. The same result was obtained after
hydrobromide ophthalmic solution) given unilaterally to the injection of L-(2)-[9-14C]scopolamine-9#-glucuronide into
lower cul-de-sac of the operated or affected eye was quantified these mammalian species. With expiring 14CO2, this
in 8 patients.5 The 2 groups, scopolamine and control placebo
group, did not differ with respect to sex distribution, age,
weight, or height. The plasma concentration (mean 6 SD) of
scopolamine was 400 6 50 pg/mL after 3 minutes and was
decreased to 120 6 20 pg/mL at 90 minutes. Cmax (mean 6
SD) was 550 6 60 pg/mL and was reached within 15 minutes
(tmax) in all but 2 patients. In these 2 subjects the peak plasma
concentration of scopolamine was at 60 minutes with a value
of 340 pg/mL, and at 30 minutes with a peak concentration of
280 pg/mL, respectively. Compared with the placebo group,
ocular scopolamine did not affect the blood pressure in
patients. Before administration the salivary secretion was
0.319 6 0.05 g in the scopolamine and 0.416 6 0.147 g in the
placebo group. Thirty minutes after eye drop application, the
secretion was reduced by 0.012 6 0.040 g in the scopolamine
and increased by 0.074 6 0.048 g (P = 0.19) in the placebo
group from the pretreatment value.

Protein Binding
The plasma protein binding of drugs has been shown to
have significant effects on numerous aspects of clinical
pharmacokinetics (PK) and pharmacodynamics (PD). Hitherto
existing measurements of the protein binding of scopolamine
are in rats and showed a low value of 30 6 10%.41

Metabolism and Excretion


Although the drug scopolamine has been used in clinical
practice for many years, little data concerning its metabolism
and renal excretion in healthy volunteers and patients have FIGURE 3. Changes in subjective alertness after scopolamine
been published up to now. (SC). From Ebert et al17 with permission.

658 q 2005 Lippincott Williams & Wilkins


Ther Drug Monit  Volume 27, Number 5, October 2005 Scopolamine Pharmacokinetics

scopolamine conjugate was also metabolized to its corre- found in feces combined with intestinal contents.44 However,
sponding nor-compound.44 neither the drug itself nor any of its metabolites were detected
The different apo compounds of the scopolamine, in feces of rats.45 Results of analogous investigations in man
L-(2)-aposcopolamine and L-(2)-aponorscopolamine, were have not been published.
shown not to be artifacts derived during the extraction of the
drug and its conjugates from the biologic matrix. L-(2)-
Aposcopolamine, a gem-substituted styrene derivative, was Factors Affecting Scopolamine
proved to be generated (dehydratation reaction) via the Pharmacokinetics
scopolamine-O-sulfate ester, which was produced by an en- In vitro studies on the interaction of scopolamine with
zymatic (sulfotransferase) reaction.46 microsomal cytochrome P-450 (CYP) have shown an
Without any structure elucidation of the educts of oxidative demethylation of the drug during incubation with
the following enzymatic reaction, a mixture of enzymes, CYP.48 The demethylation is related to the CYP3A sub-
b-glucuronidase and b-glucuronide sulfatase (eg, glusulaseTM), family.49 This result is confirmed by the in vivo investigations
was used in vitro for hydrolysis of the conjugated scopolamine using L-(2)-[9-14C]scopolamine (see above).
metabolites in mammalian urine.45 Accordingly, it is just pos- To inhibit the CYP3A enzymes efficiently, components
sible that the sulfate conjugation might have a role in the of grapefruit juice are very suitable.50,51 Here, the predominant
metabolism of the alkaloid. However, the fact that saccharo-1,4- in vivo mechanism was suggested to be located primarily in
lactone, an inhibitor of b-glucuronidase, completely inhibited the mucosa of the small intestine52 because grapefruit juice has
hydrolysis of the conjugates with b-glucuronidase/sulfatase no essential effect on drug metabolism in the liver.53
preparation indicated no or minimal excretion of sulfate con- The CYP3A activity in hepatic and intestinal micro-
jugates as in vivo metabolites of scopolamine in mammals.45 somes has been demonstrated to be greater in women than in
In addition, there was no racemization of the scopol- men.54,55 In a clinical study the influence of grapefruit juice on
amine itself or any optically active metabolites in any animal scopolamine pharmacokinetics in healthy male and female
species during passage through the organism. This result was volunteers was shown.15 When scopolamine was administered
obtained indirectly using the stereospecific (2)-hyoscyamine together with 150 mL grapefruit juice scopolamine concen-
acylhydrolase enzyme for the analysis of the optical activity of trations continued to increase for a longer period, resulting
scopolamine and its metabolites. Under the catalysis of this in an evident prolongation of tmax (59.5 6 25.0 minutes;
enzyme, an ester cleavage in the L-(2)-scopolamine structure P , 0.001). The AUC024h values of scopolamine were higher
takes place, resulting in scopine and L-(2)-tropic acid. during the grapefruit juice period. They reached approximately
The (2)-hyoscyamine acylhydrolase is contained in 142% of the values associated with the control group (water
organ homogenates and body fluids of several mammals, period; P . 0.005). Consequently, the corresponding absolute
especially in rabbit serum, but in matrices of humans the bioavailabilities of scopolamine (range 6% to 37%) were
enzyme is hardly traceable.44 significantly higher than the values after oral administration
The amounts of metabolites excreted in mammals are together with water (range 3% to 27%).
highly species specific, and their relationship is largely inde- Cmax of scopolamine administered intravenously and
pendent of the administered dose. The pharmacological ac- determined in male subjects was significantly higher compared
tivities of the identified metabolites have not been analyzed with the corresponding Cmax in female subjects. But after oral
so far. administration of scopolamine together with grapefruit juice or
Little data about the metabolism in healthy volunteers has water, no differences in the pharmacokinetic parameters of the
been published, indicating the glucuronide or sulfate conjugation drug were found between male and female subjects. Appro-
as the significant metabolic pathway of L-(2)-scopolamine. ximately 30% of the dose administered was excreted in urine
Following an incubation with b-glucuronidase/sulfatase, the as unchanged drug or as glucuronide conjugate independent of
amount of scopolamine in human urine increased from 3% the sex and of the route of administration (infusion, per os
up to approximately 30% of the drug dose (intravenously administration with water or with grapefruit juice). The
administered).15,47 However, an analysis stringently verifying elimination was not significantly affected.15
the metabolism in man is still lacking. Compared with the With regard to transdermal delivery of scopolamine, the
metabolism in mammals, it is also not evident so far how many skin temperature of the patients is not decisive. However,
different glucuronide conjugates of scopolamine and its permeation across human skin in vitro is significantly
derivatives (apo- and nor-compounds) are produced in man. intensified by increasing the scopolamine concentration or
Therefore, following a complete chromatographic analysis, the raising the pH of the diffusing drug solution.23,56
chemical structures of the metabolites isolated from human In the same manner the nasal absorption of scopolamine
urine still have to be elucidated. Scopolamine metabolites in human subjects is influenced by pH value and dosage. The
excreted in urine of mammals or man are summarized in average AUC value was found to be significantly higher for pH
Figure 5. 9.0 formulation as compared with those of pH 4.0 and pH 7.0,
Another possible route to eliminate metabolites is excre- respectively. Both the Cmax and AUC values were almost doubled
tion into feces. Verifying the excretion of the drug via the with doubling the dose. The average tmax values decreased
intestine, there are only few data. In studies describing scopo- linearly with a decrease in formulation pH at both doses.14
lamine metabolism in mice, small amounts of the unchanged Pharmacokinetics of scopolamine is able to be influenced
L-(2)-scopolamine and the scopolamine-9#-glucuronide were by oral contraceptives. Depending on the dose administered,

q 2005 Lippincott Williams & Wilkins 659


Renner et al Ther Drug Monit  Volume 27, Number 5, October 2005

the contraceptives may inhibit the metabolism of scopolamine,


decrease plasma albumin concentrations by 3% to 12%, and
may change the clearance.5759

PHARMACODYNAMICS AND ADVERSE


EFFECTS OF SCOPOLAMINE
After IV infusion, scopolamine significantly decreased
subjective alertness in both male and female subjects
compared with baseline (P , 0.05) without any differences
by sex.15,6062 Time-dependent disturbances occurred maxi-
FIGURE 4. Representative example of the concentrationEEG
effect relationship (a power) in occipital electrode positions
mally 0.52 hours after starting IV infusion of scopolamine in
after intravenous infusion of 0.5 mg scopolamine hydro- both male and female volunteers.
bromide in a healthy volunteer. Solid line represents the In addition a slight decrease in subject alertness was
optimal fit of the actual data points. Cp(t) = predicted serum observed after oral administration of scopolamine with water
concentration of scopolamine at time t. From Ebert et al20 with or grapefruit juice compared with baseline (P , 0.05) in both
permission. male and female subjects without any differences by sex.15

FIGURE 5. Metabolic pathways of L-(2)-scopolamine.

660 q 2005 Lippincott Williams & Wilkins


Ther Drug Monit  Volume 27, Number 5, October 2005 Scopolamine Pharmacokinetics

Twenty-four hours after drug administration, the sub- electrode positions) derived for an individual healthy subject
jective state was not significantly different from baseline value after IV scopolamine administration (PK-PD modeling). No
in either male or female subjects.15 time delay between serum concentrations and EEG effect was
Scopolamine orally administered shows an effectiveness observed, and the corresponding values were directly corre-
in preventing motion sickness within 0.5 hours for a period of lated to each other by a sigmoid Emax model (Emax is the maximal
6 hours. The transdermal administration of the same drug is drug effect).20
effective over a period of 72 hours. However, by this route the Scopolamine administered in pharmacologically effec-
effect is not achieved until 6 to 8 hours postapplication.9On the tive doses generates fatigue, dreamless sleep (reduction in
other hand, simultaneously with the stimulation or inhibition, rapid eye movement, REM), amnesia, vertigo, vestibular de-
respectively, of other neurotransmitters (eg, serotonergic neu- pression. In contrast, in patients receiving higher scopolamine
rotransmission63 and the dopaminergic system64), the cholin- doses, the drug can produce a stimulation of the CNS with
ergic system is involved in the storage and retrieval of symptoms, eg, excitement, hallucinations, irritability.70
information during new learning. The blockade of central The mechanism of action of the anticholinergic
muscarinic receptors induces a memory deficit in young sub- (antimuscarinic) drug scopolamine is the competitive antag-
jects that is similar to that occurring in elderly subjects.60,62,65 onism of acetylcholine at the muscarinic receptors.71 For a
Age-related changes in the central cholinergic system are better understanding of the pharmacodynamics and the di-
reflected in a decreased functional activity of cholinoreceptive versity of adverse effects caused by scopolamine, the local
neurons. In addition, studies in patients with Alzheimer dis- distribution of muscarinic receptors (a family of 5 subtypes,
ease have shown a severe loss of neurons in the nucleus basalis M1M5, is expressed in man) has to be considered. Each of the
of Meynert.66 The decrease in cortical choline acetyltransfer- human muscarinic receptor proteins (M1M5) is encoded by
ase found in Alzheimer patients is suggested to reflect a a unique gene, and its corresponding amino acid sequence has
specific loss of cholinergic input to the cortex65 because the been described.72,73 As found with PCR, receptor subtype
nucleus basalis of Meynert is believed to provide the primary mRNAs of M1 to M5 are expressed in the human brainstem,
cholinergic input to the cortical mantle.67 It is postulated that cerebellum, and cortex. In contrast, the vestibular ganglia and
postsynaptic muscarinic receptors are permanently destroyed the vestibular end organs in humans express only M1, M2, and
or inactivated in dementia of the Alzheimer type.68 In stud- M5.74 In consequence of these results and previous electro-
ies of electroencephalogram (EEG) changes and drug effects physiological and immunohistochemical analyses, the efferent
on different cognitive functions, scopolamine is commonly cholinergic axosomatic and axodentritic synapses are sug-
used as a pharmacological model substance based on the gested to have muscarinic components having an effect on
cholinergic hypothesis of memory loss in senile dementia of motion sickness.75,76
the Alzheimer type. However, the scopolamine model is Based on pharmacological studies with experimental
insufficient to indicate the full range of memory deficits found drugs, eg, pirenzepine, AFDX-116, or methocramine (each a
in patients with Alzheimer disease.69 selective antagonist), 3 subtypes (M1, M2, and M3) of muscari-
The effects of intravenously,20 intramuscularly,20,61 and nic receptors can be defined.72,77
subcutaneously17 administered scopolamine on quantitative The receptors have been found to regulate a broad range
EEG (qEEG) and cognitive performance related to pharma- of physiological and biochemical activities throughout the
cokinetic parameters were demonstrated in studies with CNS via the activation of guanidine nucleotide binding (G)
healthy volunteers. Scopolamine produced a dose- and time- proteins. Nevertheless the physiological function of these
dependent impairment of memory and attention. After admin- receptor subtypes is still poorly defined, but the anatomic
istration of scopolamine (0.40.8 mg SC), the drug generated location of the subtypes suggests that the neuronal tissues have
a time-dependent increase in d power (1.254.50 Hz) and a a preponderance of M1 receptors. The subtype M2 is situated
decrease in fast a power (9.7512.50 Hz) on qEEG for more predominantly in the heart, and M3 is the glandular sub-
than 8 hours. The temporary changes in cognitive behavior type.72,73
evaluated by qEEG and psychometric tests (eg, changes in Similar to atropine, L-(2)-scopolamine is a nonselective
choice reaction time) are shown in Figure 3. muscarinic antagonist.78 The sensitivity of the subtypes seems
Pharmacodynamic measurements after intravenous and to vary in such a way that the inhibition of salivation (M3
intramuscular scopolamine administration (0.5 mg scopol- receptors) can be produced with low doses, whereas much
amine hydrobromide over a period of 15 minutes, and 0.5 mg higher doses are needed for heart effects (M2 receptors).79,80
in the upper right arm, respectively) indicated no interday As a result of the mechanism of action described above, the
variability of the baseline values of EEG. The absolute power measured plasma levels of scopolamine do not necessarily
in a band (7.5011.25 Hz) decreased after scopolamine correlate with the pharmacodynamic effects of the drug.
administration. This effect returned gradually to baseline. The effects of scopolamine on the cardiovascular system
Fifteen minutes after beginning scopolamine infusion, are complex and dose dependent.40 Low doses of the alkaloid
a significant decrease in absolute a power occurred at frontal, give rise to a slowing of heart rate, whereas higher doses
central, and occipital brain areas compared with placebo. This produce an increase in heart rate dose-dependently. Follow-
effect was persistent up to 180 minutes after drug adminis- ing the inhibition of the vagal transmission of the sinoatrial
tration (P , 0.05).20 node, tachycardia is produced. Such a biphasic doseresponse
Figure 4 shows the relationship between scopolamine curve is prominent with scopolamine. Intravenously admin-
serum concentrations and EEG effects (a power in occipital istered doses up to 2.8 mg/kg body weight (bw) produce only

q 2005 Lippincott Williams & Wilkins 661


Renner et al Ther Drug Monit  Volume 27, Number 5, October 2005

bradycardia. After a dose of more than 8.4 mg/kg bw, a tran- after injury to the parotid gland.88 LD50 was determined in rats
sient tachycardia is observed, is reversed within 30 minutes, administered 3800 mg/kg bw subcutaneously.89 Although
and is followed by a long-lasting bradycardia.81 many epoxides have been observed to show a highly muta-
Scopolamine produces mydriasis and cycloplegia. Here, genic activity, the parasympatholytic drug scopolamine does
the sphincter muscle of the iris and the ciliary muscle of the not posses such an activity.90
lens are paralyzed.40 Eye functions may be impaired up to 7
12 days when scopolamine is administered locally. After orally
or parenterally administered scopolamine, visual problems are DOSAGE REGIMEN
both slow to develop and slow to reverse.82 In addition, only Scopolamine is used mainly in the prevention of motion
a small effect on eye pressure is described after oral or parenteral sickness, in various gastrointestinal disorders, and as premed-
scopolamine. This is in contrast to the local administration. ication before anesthesia.
However, in patients with narrow-angle glaucoma, the systemic Commercially available patches applied to the postaur-
application of L-(2)scopolamine may induce a dangerous icular area contain a scopolamine reservoir of 1.5 mg and
increase in eye pressure.40 deliver 0.5 mg of the drug over a time period of 3 days.
Scopolamine gives a rise to an inhibition of gastric Therefore, after a priming dose of 140 mg delivered in the first
salivation and secretion. The drug produces dryness of the few hours, the drug is released with a constant rate of 5 mg/h
mouth and decreases the tone of the smooth muscle in the over the following 3 days. The recommended dose applied to
gastrointestinal and urinary tract, leading to a decreased an adult is a single TTS-patch placed on the postauricular area
motility.79 at least 46 hours before an antiemetic effect is required. If
Additionally, the motility of stomach and esophagus is a shorter period is required to prevent motion sickness,
decreased. a combination of a TTS patch and a 0.3 mg tablet is intended
Adverse effects of scopolamine in the respiratory tract for administration 1 hour before travel. If there is an insuf-
are dryness of the mucous membranes of the nasopharynx, ficient clinical response, a higher dose (0.6-mg scopolamine
mouth, bronchi, and bronchioli. Following a relaxation of the tablet) has to be used. The combination of transdermal and oral
smooth muscles after scopolamine administration, the airway scopolamine is extremely efficient in achieving a fast and
resistance in the respiratory tract is reduced. prolonged prophylactic protection against motion sickness.9
Scopolamine (IV) reduces the sweat gland activity and, TTS-patch is not recommended for administration in
hence, the galvanic skin response.83 children and should be used with special caution in patients with
The tonus and the amplitude of urethra and bladder pyloric obstruction, intestinal obstruction, impaired liver and
contractions may be decreased after scopolamine application. kidney function, and urinary bladder neck obstruction. The
Therefore, there is a contraindication to the use of the drug in scopolamine patch is contraindicated in patients with plaster
patients with obstructive uropathy.40 allergy, in patients with glaucoma, and in pregnant women.
The clinical effects of scopolamine in patients un-
dergoing cesarean section under general anesthesia were
TOXICITY determined in a clinical study. Using scopolamine instead of
Because of the limited information on species differ- the routine atropine medication, 3 groups of parturients were
ences in the acute toxicity of scopolamine, it is not clear which administered the alkaloid intravenously, intramuscularly, or
metabolites contribute to the toxicity of the drug. For instance, oropharyngeally (intubated patients). The patients of group 1
in toxicity studies of atropine, the metabolite apoatropine, (IV injection) were slightly sedated only, without amnesia,
a styrene derivative, has been demonstrated to possess more and the dryness of the mouth subjectively was reported to be
potent acute toxicity than atropine itself.45,84 only moderate. In contrast, in group 2 (IM injection) and group
If the same relation between aposcopolamine and sco- 3 (oropharyngeal application), all patients were markedly
polamine obtains, the contribution of the dehydrated metab- sedated and had complete amnesia up to 1.52 hours after the
olite to the occurrence of scopolamine toxicity may be most end of the anesthesia. All of them reported a strong dryness of
significant in guinea pig because these mammals have the the mouth. According to these measured pharmacodynamics
highest dehydrating capacity among the species examined. a single intravenous dose of 5 mg scopolamine per kg bw is
The alkaloid readily crosses the placenta. Therefore, the clinically useful without prominent residual effects, but both
administration of scopolamine in pregnant women should the 10 mg/kg intramuscular and 35 mg/kg oropharyngeal doses
occur only under clinical observation.85,86 The drug is com- caused too strong adverse effects.91 Male patients scheduled
patible with nursing and is not considered to be teratogenic.87 for minor surgery under spinal anesthesia were studied.
Scopolamine toxicity has been described in a newborn with Patients received scopolamine (6 mg/kg bw) plus morphine
symptoms such as tachycardia, fever, and lethargy. (200 mg/kg bw) injected in either deltoid or gluteal muscle.
The signs and symptoms of an anticholinergic intoxi- The sedative effect of the drug combination was prominent and
cation include somnolence, coma, confusion, agitation, hallu- long lasting in both groups.6
cinations, convulsion, visual disturbance, dry flushed skin, dry
mouth, urinary retention, decreased bowel sounds, hyperten-
sion, and supraventricular arrythmias. CONCLUSION
A case of Frey syndrome is reported characterized by Scopolamine is a nonselective muscarinic antagonist.
gustatory sweating and erythema of the face on mastication The mechanism of action of the anticholinergic drug

662 q 2005 Lippincott Williams & Wilkins


Ther Drug Monit  Volume 27, Number 5, October 2005 Scopolamine Pharmacokinetics

scopolamine is the competitive antagonism of acetylcholine at tandem mass spectrometry. J Chromatogr B Biomed Sci Appl. 2001;750:
the muscarinic receptors. As a result of the nonpolar structure 121128.
11. Whelpton R, Hurst PR, Metcalfe RF, et al. Liquid chromatographic
of the native parasympatholytic drug, its good lipid solubility determination of hyoscine (scopolamine) in urine using solid phase
permits almost complete and rapid gastrointestinal absorption extraction. Biomed Chromatogr. 1992;6:198204.
and crossing of the bloodcerebrospinal fluid barrier. Scopol- 12. Auriola S, Martinsen A, Oksman-Caldentey KM, et al. Analysis of tropane
amine shows profound sedative, amnesic, and antiemetic ac- alkaloids with thermospray high-performance liquid chromatography
mass spectrometry. J Chromatogr. 1991;562:737744.
tions. Because of the large number of adverse effects and 13. Mateus L, Cherkaoui S, Christen P, et al. Capillary electrophoresis-diode
the short duration of action following oral, intravenous, or array detectionelectrospray mass spectrometry for the analysis of
intramuscular administration, the clinical use is limited. selected tropane alkaloids in plant extracts. Electrophoresis. 1999;20:
Nevertheless, scopolamine is the most effective single agent 34023409.
to prevent motion sickness. To minimize the relatively high 14. Ahmed S, Sileno AP, de Meireles JC, et al. Effects of pH and dose on nasal
absorption of scopolamine hydrobromide in human subjects. Pharm Res.
incidence of adverse effects and to extend the duration of 2000;17:974.
action, the TTS-patch was developed. In several studies TTS- 15. Ebert U, Oertel R, Kirch W. Influence of grapefruit juice on scopolamine
patches have been shown to reach protective levels after 68 pharmacokinetics and pharmacodynamics in healthy male and female
hours, achieving a steady state. The optimal efficacy is subjects. Int J Clin Pharmacol Ther. 2000;38:523531.
16. Bayne WF, Tao FT, Crisologo N. Submicrogram assay for scopolamine in
maintained over a period of 72 hours. In contrast, scopolamine plasma and urine. J Pharm Sci. 1975;64:288291.
administered orally or intravenously shows an effectiveness in 17. Ebert U, Siepmann M, Oertel R, et al. Pharmacokinetics and
preventing motion sickness within 0.5 hours for a period of pharmacodynamics of scopolamine after subcutaneous administration.
only 6 hours. However, its bioavailability is limited after oral J Clin Pharmacol. 1998;38:720726.
administration. The glucuronide conjugation of scopolamine 18. Deutsch J, Soncrant TT, Greig NH, et al. Electron-impact ionization
detection of scopolamine by gas chromatographymass spectrometry in
could be the relevant pathway in a healthy human. This will be rat plasma and brain. J Chromatogr. 1990;528:325331.
suggested by the results of the enzymatic hydrolysis of con- 19. Oertel R, Richter K, Ebert U, et al. Determination of scopolamine in
jugated metabolites with b-glucuronidase and sulfatase. How- human serum by gas chromatographyion trap tandem mass spectrometry.
ever, scopolamine metabolism in humans is not completely J Chromatogr B Biomed Appl. 1996;682:259264.
20. Ebert U, Grossmann M, Oertel R, et al. Pharmacokinetic-pharmacodynamic
known, and a complete chromatographic analysis followed by modelling of the electroencephalogram effects of scopolamine in healthy
elucidation of the exact chemical structures of the metabolites volunteers. J Clin Pharmacol. 2001;41:5160.
extracted from human urine is still lacking. 21. Shaw JE, Crammer MP, Gale R. Rate-controlled transdermal therapy
Inhibiting the CYP3A enzyme with components of using polymeric membranes. In: Kydonieus AF, Berner B, eds: Transdermal
grapefruit juice influences the pharmacokinetics of scopolamine Delivery of Drugs, Vol. I. Boca Raton, FL: CRC Press, 1987, pp 101
116.
to produce evident prolongation of tmax, and the AUC024h 22. Berner B, John VA. Pharmacokinetic characterisation of transdermal
values and consequently the bioavailabilities of scopolamine delivery systems. Clin Pharmacokinet. 1994;26:121134.
were significantly higher. 23. Shaw JE, Chandrasekaran SK, Campbell PS, et al. New procedures for
evaluating cutaneous absorption. In: Drill VA, Lazar P, eds. Cutaneous
Toxicity. Proceedings of the 3rd Conference of the American Medical
Association, 1976. New York: Academic Press, 1977, pp 8394.
REFERENCES 24. Shaw JE, Chandrasekaran SK, Taskovich L. Use of percutaneous
1. Ali-Melkkila T, Kanto J, Iisalo E. Pharmacokinetics and related absorption for systemic administration of drugs. The Pharmaceutical
pharmacodynamics of anticholinergic drugs. Acta Anaesthesiol Scand. Journal. 1975;215:325328.
1993;37:633642. 25. Muir C, Metcalfe R. A comparison of plasma levels of hyoscine after
2. Ridout G, Santus GC, Guy RH. Pharmacokinetic considerations in the use oral and transdermal administration. J Pharm Biomed Anal. 1983;1:363
of newer transdermal formulations. Clin Pharmacokinet. 1988;15:114 367.
131. 26. Ensing K, de Zeeuw RA, Ensing GJ. Pharmacokinetics of free and
3. Putcha L, Tietze KJ, Bourne DW, et al. Bioavailability of intra- glucuronidated scopolamine following transdermal delivery of scopol-
nasal scopolamine in normal subjects. J Pharm Sci. 1996;85:899 amine in children. [abstract] Acta Pharmacol Toxicol (Copenh). 1986;
902. 59(Suppl. 5):81.
4. Klocker N, Hanschke W, Toussaint S, et al. Scopolamine nasal spray in 27. Ensing K, int Hout WG, Halma P, et al. Development and application of
motion sickness: a randomised, controlled, and crossover study for the a radioreceptor assay for scopolamine. Arzneimittelforschung. 1988;38:
comparison of two scopolamine nasal sprays with oral dimenhydrinate 106111.
and placebo. Eur J Pharm Sci. 2001;13:227232. 28. Bosman IJ, Douma WR, Ensing K, et al. A semi-automated solid-phase
5. Lahdes K, Huupponen R, Kaila T, et al. Systemic absorption of ocular extraction and radioreceptor assay for the analysis of scopolamine in urine
scopolamine in patients. J Ocul Pharmacol. 1990;6:6166. and plasma. Eur J Pharm Sci. 1997;5:315325.
6. Kentala E, Scheinin H, Kaila T, et al. Pharmacokinetics and clinical effects 29. Schmitt LG, Shaw JE, Carpenter PF, et al. Comparison of transdermal and
of intramuscular scopolamine plus morphine. A comparison of two intravenous administration of scopolamine. [abstract] Clin Pharmacol
injection sites. Acta Anaesthesiol Scand. 1998;42:323328. Ther. 1981;29:282.
7. Kanto J, Klotz U. Pharmacokinetic implications for the clinical use of 30. Chandrasekaran SK, Bayne W, Shaw JE. Pharmacokinetics of drug
atropine, scopolamine and glycopyrrolate. Acta Anaesthesiol Scand. permeation through human skin. J Pharm Sci. 1978;67:13701374.
1988;32:6978. 31. Graybiel A, Knepton J, Shaw J. Prevention of experimental motion
8. Aaltonen L, Kanto J, Iisalo E, et al. Comparison of radioreceptor assay and sickness by scopolamine absorbed through the skin. Aviat Space Environ
radioimmunoassay for atropine: pharmacokinetic application. Eur J Clin Med. 1976;47:10961100.
Pharmacol. 1984;26:613617. 32. Pyykko I, Schalen L, Jantti V. Transdermally administered scopolamine
9. Nachum Z, Shahal B, Shupak A, et al. Scopolamine bioavailability in vs. dimenhydrinate. I. Effect on nausea and vertigo in experimentally
combined oral and transdermal delivery. J Pharmacol Exp Ther. 2001; induced motion sickness. Acta Otolaryngol. 1985;99:588596.
296:121123. 33. Homick JL, Kohl RL, Reschke MF, et al. Transdermal scopolamine in the
10. Oertel R, Richter K, Ebert U, et al. Determination of scopolamine in prevention of motion sickness: evaluation of the time course of efficacy.
human serum and microdialysis samples by liquid chromatography Aviat Space Environ Med. 1983;54:9941000.

q 2005 Lippincott Williams & Wilkins 663


Renner et al Ther Drug Monit  Volume 27, Number 5, October 2005

34. Parrott AC, Jones R. Effects of transdermal scopolamine upon 57. Juchau MR, Fouts JR. Effects of norethynodrel and progesterone on
psychological test performance at sea. Eur J Clin Pharmacol. 1985;28: hepatic drug-metabolizing enzyme systems. Biochem Pharmacol. 1966;
419423. 15:891898.
35. Graybiel A, Cramer DB, Wood CD. Experimental motion sickness: 58. Song CS, Merkatz IR, Rifkind AB, et al. The influence of pregnancy and
efficacy of transdermal scopolamine plus ephedrine. Aviat Space Environ oral contraceptive steroids on the concentration of plasma proteins. Am J
Med. 1981;52:337339. Obstet Gynecol. 1970;108:227231.
36. Doweck I, Dachir S, Spitzer O, et al. Rate of absorption of scopolamine 59. Wilson K. Sex-related differences in drug disposition in man. Clin
after application of Scopoderm-TTS. [abstract] Aviat Space Environ Med. Pharmacokinet. 1984;9:189202.
1995;66:467. 60. Ghoneim MM, Mewaldt SP. Studies on human memory: the interaction of
37. Doweck I, Nachum Z, Dachir S, et al. Enhancement of transdermal diazepam, scopolamine, and physostigmine. Psychopharmacology (Berl).
scopolamine absorption using sonophoresis [abstract]. In: Program and 1977;52:16.
Abstracts, 44th International Congress of Aviation and Space Medicine, 61. Sannita WG, Maggi L, Rosadini G. Effects of scopolamine (0.250.75 mg
Jerusalem, Israel, 1996:p 18. i.m.) on the quantitative EEG and the neuropsychological status of healthy
38. Cintron NM, Chen YM. A sensitive radioreceptor assay for determining volunteers. Neuropsychobiology. 1987;17:199205.
scopolamine concentrations in plasma and urine. J Pharm Sci. 1987;6: 62. Wesnes KA. An investigation of the range of cognitive impairments
328332. induced by scopolamine0.6 mg s.c. Hum Psychopharmacol. 1988;3:
39. Parrott AC. Transdermal scopolamine: a review of its effects upon motion 2741.
sickness, psychological performance, and physiological functioning. Aviat 63. Blokland A. Acetylcholine: a neurotransmitter for learning and memory?
Space Environ Med. 1989;60:19. Brain Res Rev. 1996;21:285300.
40. Clissold SP, Heel RC. Transdermal hyoscine (scopolamine). A pre- 64. Dunnett SB, Robbins TW. The functional role of the mesotelencephalic
liminary review of its pharmacodynamic properties and therapeutic dopamine systems. Biol Rev. 1992;67:491518.
efficacy. Drugs. 1985;29:189207. 65. Bartus RT, Dean RL, Beer B, et al. The cholinergic hypothesis of geriatric
41. Nakashima E, Ishizaki J, Takeda M, et al. Pharmacokinetics of memory dysfunction. Science. 1982;217:408417.
anticholinergic drugs and brain muscarinic receptor alterations in 66. Whitehouse PJ, Price DL, Clark AW, et al. Alzheimer disease: evidence
streptozotocin diabetic rats. Biopharm Drug Dispos. 1993;14:673 for selective loss of cholinergic neurons in the nucleus basalis. Ann
684. Neurol. 1981;10:122126.
42. Putcha L, Cintron NM, Tsui J, et al. Pharmacokinetics and oral 67. Wenk H, Bigl V, Meyer U. Cholinergic projections from magnocellular
bioavailability of scopolamine in normal subjects. Pharm Res. 1989;6: nuclei of the basal forebrain to cortical areas in rats. Brain Res. 1980;2:
481485. 295316.
43. Kanto J, Kentala E, Kaila T, et al. Pharmacokinetics of scopolamine 68. Sunderland T, Tariot PN, Cohen RM, et al. Anticholinergic sensitivity in
during caesarean section relationship between serum concentration and patients with dementia of the Alzheimer type and age-matched controls:
effect. Acta Anaesthesiol Scand. 1989;33:482486. a dose-response study. Arch Gen Psychiat. 1987;44:418426.
44. Werner G, Schmidt KH. [Studies on the metabolism of tropane alkaloids. 69. Ebert U, Kirch W. Scopolamine model of dementia: electroencephalo-
8. Chemical analysis of (2)-scopolamine metabolism in several mammals] gram findings and cognitive performance. Eur J Clin Invest. 1998;28:
Hoppe Seylers Z Physiol Chem. 1968;349:741752. 944949.
45. Wada S, Yoshimitsu T, Koga N, et al. Metabolism in vivo of the tropane 70. Brown JH, Taylor P. Muscarinic receptor agonists and antagonists. In:
alkaloid, scopolamine, in several mammalian species. Xenobiotica. 1991; Hardman JG, Limbird LE, Molinoff PB, et al. eds: Goodman and
21:12891300. Gilmans the Pharmacological Basis of Therapeutics, 9th ed. New York:
46. Wada S, Shimizudani T, Yamada H, et al. Sulphotransferase-dependent McGraw-Hill, 1996:pp 141160.
dehydration of atropine and scopolamine in guinea pig. Xenobiotica. 71. Weiner N. Atropine, scopolamine and related antimuscarinic drugs. In:
1994;24:853861. Gilman AC, Goodman LS, Rall TW, et al. eds: The Pharmacological
47. Kentala E, Kaila T, Ali-Melkkila T, et al. beta-Glucuronide and sulphate Basis of Therapeutics. New York: Macmillan, 1985:pp 130144.
conjugation of scopolamine and glycopyrrolate. Int J Clin Pharmacol 72. Bonner TI, Buckley NJ, Young AC, et al. Identification of a family of
Ther Toxicol. 1990;28:487489. muscarinic acetylcholine receptor genes. Science. 1987;237:527532.
48. Peeples A, Dalvi RR. Toxic alkaloids and their interaction with 73. Peralta RG, Winslow JW, Ashkenazi A, et al. Structural basis of
microsomal cytochrome P-450 in vitro. J Appl Toxicol. 1982;2:300 muscarinic acetylcholine receptor subtype diversity. Trends Pharmacol
302. Sci. 1988;Suppl III:711.
49. Ristau O, Wagnerova DM, Rein H, et al. Demethylation of tertiary amines 74. Wackym PA, Chen CT, Ishiyama A, et al. Muscarinic acetylcholine
by a reconstituted cytochrome P-450 enzyme system: kinetics of oxygen receptor subtype mRNAs in human and rat vestibular periphery. Cell Biol
consumption and hydrogenperoxide formation. J Inorg Biochem. 1989; Int. 1996;20:187192.
37:111118. 75. Gowans J, Matheson A, Darlington CL, et al. The effects of scopolamine
50. Bailey DG, Arnold JM, Spence JD. Grapefruit juice and drugs. How and cyclizine on visualvestibular interaction in humans. J Vestib Res.
significant is the interaction? Clin Pharmacokinet. 1994;26:9198. 2000;10:8792.
51. Fuhr U, Kummert AL. The fate of naringin in humans: A key to 76. Gacek RR. Efferent innervation of the labyrinth. Am J Otolaryngol. 1984;
grapefruit juice-drug interactions? Clin Pharmacol Ther. 1995;58: 5:206224.
365373. 77. Birdsall NJM, Curtis CAM, Eveleigh P, et al. Muscarinic receptor
52. Kivisto KT, Bookjans G, Fromm MF, et al. Expression of CYP3A4, subtypes and the selectivity of agonists and antagonists. Pharmacology.
CYP3A5 and CYP3A7 in human duodenal tissue. Br J Clin Pharmacol. 1988;37:2231.
1996;42:387389. 78. Wellstein A, Pitschner HF. Complex doseresponse curves of atropine in
53. Fuhr U. Drug interactions with grapefruit juice. Extent, probable man explained by different functions M1- and M2-cholinoceptors.
mechanism and clinical relevance. Drug Saf. 1998;18:251272. Naunyn Schmiedebergs Arch Pharmacol. 1988;338:1927.
54. Hunt CM, Westerkam WR, Stave GM. Effect of age and gender on the 79. Mirakhur RK, Dundee JW. Gycopyrrolate: pharmacology and clinical use.
activity of human hepatic CYP3A. Biochem Pharmacol. 1992;44:275 Anaesthesia. 1983;38:11951204.
283. 80. Ali-Melkkila T, Kaila T, Kanto J. Glycopyrrolate: pharmacokinetics and
55. Lown KS, Kolars JC, Thummel KE, et al. Interpatient heterogeneity in some pharmacodynamic findings. Acta Anaesthesiol Scand. 1989;33:
expression of CYP3A4 and CYP3A5 in small bowel. Lack of prediction 513517.
by the erythromycin breath test. Drug Metab Dispos. 1994;22:947955. 81. Gravenstein JS, Thornby JI. Scopolamine on heart rate in man. Clin
Erratum in: Drug Metab Dispos. 1995;23. Pharmacol Ther. 1968;10:395400.
56. Shaw JE, Chandrasekaran SK. Transdermal therapeutic systems. In: 82. Mirakhur RK. Comparative study of the effects of oral and i.m. atropine
Prescott LF, Nimmo WS, eds. Drug Absorption: The Proceedings of the and hyoscine in volunteers. Br J Anaesth. 1978;50:591598.
International Conference on Drug Absorption; Edinburgh, September, 83. Turner P. Test of autonomic function in assessing centrally-acting drugs.
1979. New York: ADIS Press, 1981:pp 186193. Br J Clin Pharmacol. 1980;10:9399.

664 q 2005 Lippincott Williams & Wilkins


Ther Drug Monit  Volume 27, Number 5, October 2005 Scopolamine Pharmacokinetics

84. Krantz JC Jr, Forrest JW, Heisse CK. Contribution to the pharmacology of 88. Bednarek J, Reid W, Matsumoto T. Freys syndrome. Am J Surg. 1976;
apoatropine and its methyl bromide. Proc Soc Exp Biol Med. 1954;86: 131:592594.
511512. 89. Stockhaus K, Wick H. Studies of the toxicity of drugs in subcutaneous,
85. Ayromlooi J, Tobias M, Berg P. The effects of scopolamine and ancillary intragastric and intraduodenal administration in rats. Arch Int Pharma-
analgesics upon the fetal heart rate recording. J Reprod Med. 1980;25: codyn Ther. 1969;180:155161.
323326. 90. Glatt H, Jung R, Oesch F. Bacterial mutagenicity investigation of
86. Evens RP, Leopold JC. Scopolamine toxicity in a newborn. [letter] epoxides: drugs, drug metabolites, steroids and pesticides. Mutat Res.
Pediatrics. 1980;66:329330. 1983;111:99118.
87. Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in Pregnancy and 91. Pihlajamaki KK, Kanto JH, Oksman-Caldentey KM. Pharmacokinetics
Lactation: A Reference Guide to Fetal and Neonatal Risk, 4th ed. and clinical effects of scopolamine in caesarean section patients. Acta
Baltimore: Williams & Wilkins, 1994:pp 777778. Pharmacol Toxicol (Copenh). 1986;59:259262.

q 2005 Lippincott Williams & Wilkins 665