The importance of lipid solubility in membrane permeation

Routes by which solutes can traverse cell membranes

Theoretical partition of a weak acid (aspirin) and a weak base (pethidine) between aqueous
compartments (urine, plasma and gastric juice) according to the pH difference between them.
The effect of urinary pH on drug excretion
The main routes of drug administration and elimination
The two phases of drug metabolism
Stimulation of hepatic metabolism of benzpyrene
The glucuronide conjugation reaction
Predicted behaviour of single-compartment model with continuous or
intermittent drug administration
To achieve a steady state plasma concentration (Css)

Drug entry = Drug exit

Dosing rate = Excretion rate
Dosing rate = Css x Clearance Clearance = Vd x ke
Dosing rate = Css x (ke x Vd)/F ke = 0.693/ t1/2
Dosing rate = Css x (0.693 x Vd)/F
t1/2
t1/2 = 0.693 x Vd/Clearance = 0.693/ke
Drug T needs to be given intravenously:
Clearance = 70 ml/min
Desired plasma concentration = 3 mg/L

Maintaenance dose = ?????

Dosing rate = Clearance x Desired plasma concentration/F

Dosing rate = 70 ml/min/1000 x 3 mg/L = 0.21 mg/min

Multiple Doses

Drug T needs to be given intravenously every 5 hours:

Clearance = 70 ml/min
Desired plasma concentration = 3 mg/L

Dosing rate = Cl x Css x Dosing interval /F

Dosing rate = 70 ml/min/1000 x 3 mg/L x (5hr)

= 70 ml/min/1000 x 3 mg/L x (300 min)
= 63 mg every 5 hours
Loading dose = ??????

Vd = 50 L
Desired plasma concentration = 3 mg/L

Loading dose = Vd x Desired plasma concentration

= 3mg/L x 50L
= 150 mg

Note: LD = 1.44 x Css x Vd (more accurate calculation)

F
First Order Kinetics
Rate of elimination is directly proportional to the
drug cocentration
dC/dt α C dC/dt = -ke x C

(C1, t1)

Cp Log Cp
(C2, t2)

Time Time

C 2= C 1 x e-ke x t C 1= C 2 x eke x t
t = t2 - t1
A patient’s acetaminophen level
at 2:00 PM is 86.2 μg/ml
at 6:00 PM the same day is 27.8 μg/ml
ke = 0.283 h-1

What was the level at 10:00 AM?

C1 = C2 x e ke x t

C1 = 86.2 x e 0.283 x 4

C1 = 267.3 μg/ml
A patient’s acetaminophen level
at 2:00 PM is 86.2 μg/ml
at 6:00 PM the same day is 27.8 μg/ml

What is Ke?

C1 = C2 x e ke x t C1 = e ke x t ln C1 = ke x t
C2 C2
ln 86.2 = ke x 4
27.8
ke = 0.283 h-1
A patient’s acetaminophen level
at 9:00 AM is 250 μg/ml. What is the level at 5:00 PM
the same day? (C2 = C1 x e -ke x t )
ke = 0.283 h-1

F. 27 μg/ml
G. 26 μg/ml
H. 252 μg/ml
I. 28 μg/ml
If the t1/2 of drug T is 6 hrs. What would u expect the
t1/2 of drug T to be in a patient with kidney failure?

D. < 6 hrs
E. > 6 hrs
F. = 6 hrs
G. non of the above
Which of the following statements is CORRECT?

C. Weak bases are absorbed efficiently across the

epithelial cells of the stomach
B. Potency of a drug may be reduced if the drug is ionized
at physiologic pH
C. Alkalinization of the urine enhances the exretion
of weak bases
D. All of the above
The addition of glucuronic acid to a drug

C. decreases the polar nature of the drug

D. increases the rate of excretion of the drug
E. is an example of a Phase 1 reaction
F. involves cytochrome P-450
A drug, given as a 100 mg single dose, results
in a peak plasma concentration of 20 µg/ml.
The Vd is:

E. 0.5 L
F. 1 L
G. 2 L
H. 5 L
Drugs showing zero-order kinetics of elimination

C. decrease in concentration exponentially with time

D. show a plot of drug concentration versus time that is
linear
C. show a constant fraction of the drug eliminated
per unit time
D. Non of the above
Which of the following statements is CORRECT
for a drug whose elimination from plasma shows
first-order kinetics?

E. The t1/2 of the drug is proportional to the drug conc.

F. The amount eliminated per unit time is constant.
C. The rate of elimination is proportional to the Cp
D. A plot of drug concentration versus time is a straight
line
If the Vd for the drug is small. This means that:

C. most of the drug is in the extraplasmic space

B. higher dose can be tolerated
C. most of the drug is in the plasma
D. B & C
Induction of hepatic metabolizing enzymes

C. results in an increase in a drug t1/2

D. results in a decrease in the rate of cyt P450 synthesis
E. leads to drug tolerance and the dosage may need to be
increased
D. All of the above
Assume that a drug has a t1/2 of 6 hrs. How long will it
take for 87.5% of the drug to be cleared from the body?

D. 6 hrs
E. 12 hrs
F. 18 hrs
G. 24 hrsc
All of the following statements are correct EXCEPT?

C. Drugs with low partition coefficient are likely to

to distribute in the plasma
B. The more lipophilic a drug is, the lower is its partition
coefficient
C. Drugs with high partition coefficient will distribute in
the adipose tissue
D. A & C