that the absorption, elimination, distribution, clearance, bioavailability,t1/2and
Vdof all existing and new drugs must be defined using preclinical trials. In
theory, all these parameters can be scaled up from animal experiments to predict
the behaviour of the substance in humans, but the correlation is usually only
approximate. The same parameters are required for Phase I trials. Phase I
results for bioavailability andt1/2are used by the pharmaceutical industry as
part of the evidence for deciding whether further investigation of a potential
drug would be justified. Phase I trials are also used to predict appropriate dose
levels for the expected patient community.
Once the drug has been found to be safe and effective in the Phase I trials, the
evaluation of pharmacokinetic parameters is required for the diseased state, age
(young and old) and gender in the Phase II trials. It is especially important to
determine the effect of reduced liver and kidney function on the elimination of
the new drug in order to avoid toxic effects due to the use of too high a dose level
in patients with these conditions. All this information is used to develop effective
safe dosage forms for new drugs and to check new dosage forms for existing
drugs.
8.7 Questions
(1) Explain the meaning of each of the following terms: (a) therapeutic window;
(b) IV bolus; (c) clearance and (d) first pass effect.(2)
OCOCH 3
OCOCH 3(A)Megestrol acetate (A) is an oral contraceptive. What pharmacokinetic
parameters should be determined for other potential oral contraceptives in
order to compare their actions with compound A? Give reasons for your
choice.(3) A patient was given a single dose of 30 mg of a drug by an IV bolus injection.
The drug plasma concentration was determined at set time intervals, the data
obtained being recorded in Table 8.4. Calculate:(i) the value of the elimination constant of the drug,
178 PHARMACOKINETICS