Fundamentals of Medicinal Chemistry

Chapter 8

(1) See Sections (a) 8.2, (b) 8.4.1, (c) 8.4.2, (d) 8.5.

(2) Absolute bioavailability (Equation (8.28) ) and half-life (Equation (8.5) ) as a meas-

ure of the rate of elimination. These parameters would give an indication of the

relative effectiveness of each of the compounds. Absolute bioavailability would

indicate the compound with the best absorption characteristics, whilst half-life

would show which compound was the most stablein situand so would have the

best chance of being therapeutically effective.

(3) Plot a graph of logCagainstt. The slope is equal tokel/2.303. (i) 1.84 h

 1

, (ii)

4.12 dm

3

, (iii) 7.58 dm

3

h

 1

. The assumption made is that the elimination exhibits
first order kinetics.

(4) At one minute, if the clearance rate is 5 cm

3

min

 1

,5cm

3

will be clear of the drug,

that is, 5/50 of the drug will have been removed, leaving 45 mg of the drug in the

compartment. In the next minute another 5/50th of the remaining amount of the

drug will be removed, as the clearance rate is constant, but this will be removed

from the 45 mg, leaving 40.5 mg, and so on. The figures corresponding to the times

are

Time lapse (minutes): 1 2 3 4 5 6 7 8 9 10

Drug remaining (mg): 45 40.5 36.5 32.8 29.5 26.5 23.8 21.4 19.3 17.4

A logarithmic plot using logarithms tobase 10of the concentration against time is a

straight line with a slope of 0.4584. Assuming a first order elimination process, the

value ofkel(see Figure 8.6) calculated from this slope is

2 : 303  0 : 4584 ¼ 1 : 056

and the value oft1/2calculated fromkelusing Equation (8.5) is 0.0656 minutes.

(5) Absolute bioavailability is defined by Equation (8.28); the values of the IV data

required are the answers to question (3).

(1) Calculate the AUC for the intravenously administered dose by substituting

Equation (8.10) in Equation (8.12). This gives

AUC for the IV¼

administered dose

Vdkel

¼

30

4 : 12  1 : 84

¼ 3 : 96

ANSWERS TO QUESTIONS 267