Influence of First~Pass Effect on the

Systemic Availability of Propoxyphene

DONALD PERRIER. M.S•• and MILO GIBALDI. Ph.D. Buffalo. N.Y.

extent to which an orally admin- where f is the fraction of drug admin-

Tistered
HE
drug reaches the systemic cir-
culation can be defined as its systemic or
physiologic availability. For a drug to be
totally available systemically, it must be
fully released from the dosage form and
completely absorbed by passage from the
lumen into the gastrointestinal mucosa
and transported through the mucosal
epithelia into the mesenteric veins, and
into and through the liver via the hepatic
portal vein, without being altered. A lack
of systemic availability may be the result
of unsatisfactory release characteristics
of a drug from its dosage form, as illus-
trated by chloramphenicol, 1 or due to
poor permeability properties, as shown by
the quaternary ammonium compounds
methyl- and butylseopolamine.v" Other
drugs such as propranolol," acetylsalicylic
acid," and Iidoeaine.s although they may
show excellent release and permeability
characteristics, have a reduced systemic
availability due to metabolism on passage
across the gut wall or through the liver.
In many cases, the systemic availability
of a drug can be determined by compar-
ing the areas under the plasma concentra-
tion-versus-time curves after oral and in-
travenous administration of equivalent
doses; i.e.,
(1)
From the Department of Pharmaceutics, School
of Pharmacy, State University of New York at
Buffalo, Buffalo, N.Y. 14214.
November-December, 1972
istered orally that actually reaches the
systemic circulation, t is time, and
c.: andfo~i.v.dt are the respec-
tive areas under the plasma level-time
curves from t=O to t= 00 after oral and
intravenous drug administration. A value
of f in equation (1) less than unity is
indicative of less than complete sys-
temic availability, which may be due to
permeability or formulation factors or
metabolism of the drug by the gut or
liver before reaching the systemic circu-
lation.
Metabolism of a drug on its initial
pass through the liver has been termed
the "first pass" effect. 7 The pharma-
cokinetic implications of the first-pass
phenomenon have been considered in
some detail, and equations have been de-
veloped to permit an estimate of the
degree to which this phenomenon occurs
with a given drug. s.9 For many systems,
the following relationship has been found"
to be quite useful:
1=1- dose (2)
l~l.v.dt • flow rate
where t and fa:> C r.v.dt are as defined
previously, "dose" is the intravenous dose,
and "flow rate" is the hepatic blood flow
rate. The f value in equation (2) is a
maximal estimate of the fraction of an
orally administered dose which would be
systemically available, since it does not
4:49
 PERRIER .AND GIB.ALDI
account for such factors as incomplete
release of drug from the dosage form,
incomplete absorption, or extrahepatic
metabolism of the drug.
The present study concerns a pharma-
cokinetic analysis of reported serum level
data for propoxyphene following oral
and intravenous administration.l'' In the
original study, eight normal adult subjects
each received at appropriate intervals 50
mg propoxyphene hydrochloride intra-
venously, and 65 and 130 mg of the
hydrochloride salt and 100 and 200 mg of
the napsylate salt orally. Seven of the
eight subjects were also given 195-mg and
300-mg oral doses of the hydrochloride
and napsylate salts, respectively. Pro-
poxyphene levels in the plasma were
measured as a function of time.
The literature data enabled the cal-
culation of the areas under the plasma
level-time curves for each dosage form.
Areas were evaluated by means of the
trapezoidal rule after extrapolation of
each curve to time infinity. The fraction
of drug reaching the systemic circulation,
as predicted by equation (2), was cal-
culated employing the data obtained from
the 50-mg intravenous injection using a
hepatic blood flow rate of 1.7 l./min. 11
These calculated f values are shown in
Table I. In seven subjects, the use of
equation (2) suggests that the oral ad-
ministration of an equivalent dose of
propoxyphene will at best provide a
plasma level-time curve area which is 32
to 63 per cent of that determined after
intravenous administration. In one addi-
tional subject, the intravenous data indi-
cates that virtually none of the orally ad-
ministered propoxyphene will be sys-
temically available. Therefore, assuming
the validity of equation (2), one would
estimate that on the average, a maximum
of 41 per cent of an orally administered
dose would reach the systemic circulation
provided that the entire dose was released,
absorbed, and not metabolized by extra-
450
hepatic enzyme systems before reaching
the liver.
The actual systemic availability of the
hydrochloride and napsylate salts upon
oral administration was determined by
means of a modification of equation (1),
viz.,
f .£ooCodt/oral dose (3)
foooCl.vodt/I.V. dose
The calculated availability data are shown
in Table I.
There was no significant difference in
systemic availability between equivalent
doses of propoxyphene as the hydro-
chloride and napsylate salts at all three
dosage levels. Furthermore, the intrasub-
jeet variability in the availability of
propoxyphene at any given dose level
from the two different salt forms was re-
markably low relative to the intersubject
variability.
The systemic availability of a 65-mg
dose of propoxyphene was found to be
about 18 per cent. Doubling the dose to
130 mg resulted in a highly significant in-
crease (P<O.OOl, Student's paired t-test)
in availability to 28 per cent of the ad-
ministered dose. A further increase in
dose to 195 mg produced a modest but
significant enhancement (P<O.Ol) in the
systemic availability to 33 per cent. While
the present results indicate a relatively
low systemic availability of propoxy-
phene, a previous study 12 based on 14 0
levels in the body suggests that an oral
dose of propoxyphene is substantially ab-
sorbed. The first-class equation, equation
(2), predicts that only 40 per cent of an
orally administered dose of propoxyphene
would be available systemically. There-
fore, even if propoxyphene is totally ab-
sorbed, 60 per cent of the dose would be
expected to be metabolized on the first
pass through the liver.
The difference between the predicted
and experimentally determined systemic
The Journal of Cliniea1 Pharmacology
 ~
I:'
r
r~
......
TABLE I
Systemic Availability* of Propoxyphene After Oral Administration
, Availability
~
co
~
65 mg* 130 mgt 195 mgt predicted by tQ
to
Subjeett HOI N HOI N HOI N first-pass equations" ~
~
I
2
0.19
0.22
0.18
0.13
0.34
0.40
0.38
0.37
0.39
-*. _..
0.43 0.32
0.63
~
C
~
3 0.14 0.19 0.25 0.21 0.27 0.19 0.00 ~
~
4 0.12 0.06 0.18 0.19 0.30 0.30 0.40 t::
~
5 0.37 0.35 0.40 0.38 0.58 0.62 0.53 ~
6 0.05 0.07 0.09 0.07 0.07 0.14· 0.34 t::
~

7 0.08 0.15 0.28 0.27 ~ 0.30 0.50 -s

Iooq
8 0.24 0.22 0.33 0.29 0.36 ~ 0.56 o
~
Mean 0.18 0.17 0.28 0.27 0.33 0.33 0.41
Standard
~
o
deviation 0.10 0.09 0.11 0.11 0.17 0.17 0.20 ~
~
Iooq
• Ratio of area under the plasma curve after oral. administration to that after intravenous administration, assuming equivalent doses, see equation (3).
t Data obtained from reference 10. ~~
t Dose is given in terms of propoxyphene hydrochloride equivalents; HOI = hydrochloride salt; N = napsylate salt.
• - Equation (2), based on a llow rate of 1.7 1./min. 11 Use of a blood llow rate of 1.53 I./min, as suggested by Bradley,13 yields a mean availability
prediction of 0.36. =
••• This subject did not participate in the study.
f Data did not permit analysis.

~
~
 PERRIER .AND GIB.ALDI
availability, summarized in Table I, could
be due to permeability or formulation
factors, extrahepatic metabolism of pro-
poxyphene prior to its initial pass
through the liver, or somewhat defective
assumptions in the pharmacokinetic
model, particularly with respect to dose-
independent kinetics and blood flow rate-
limited transfer of drug from the sys-
temic circulation to the liver. The in-
crease in systemic availability with in-
creasing oral doses suggests the possibility
that propoxyphene may' be subject to
saturable extrahepatic metabolism at the
level of the gastrointestinal lumen or
mucosa.
As indicated by the present report,
the relatively high clearance of pro-
poxyphene by the first-pass effect will di-
minish its systemic availability appreci-
ably when it is administered orally. Al-
teration of the formulation would prob-
ably do little to improve the systemic
availability of propoxyphene. Therefore,
to achieve an equivalent clinical response
to that observed after administration of a
given dose intravenously, the oral dose
would have to be significantly larger. If
toxicity is demonstrated by metabolites of
propoxyphene, the oral route of adminis-
tration may result in an increased inci-
dence of side effects.
Summary
Pharmacokinetic analysis of literature
data on drug plasma levels after oral and
intravenous administration suggests that
propoxyphene has a relatively low sys-
temic availability. The results indicate
that the lack of availability can be at-
tributed primarily to metabolism of
propoxyphene on its first pass through the
liver.
Acknowledgments
This study was supported in part by a
studentship from the Medical Research Coun-
cil of Canada. The authors wish to thank Dr.
Wolen and his associates for their helpful
discussions.
452
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The Journal of Clinical Pharmaeology