Investigation of some clinical pharmacokinetic factors in Kenyan Africans
Abstract
This is the first broad based clinical pharmacokinetics study carried out in Africans aimed at
determining whether disease states have an influence on the pharmacokinetics of xenobiotics.
It has been shown, in this study that disease states can influence the pharmacokinetics of
xenobiotics.
The well known model drug antipyrine, was chosen as the reference drug. The currently most
used beta-receptor blocker, pindolol, was chosen because of the existing controversy of poor
response by blacks to beta-blockers in treatment of hypertension. Cyclophosphamide was
chosen because of its wide use in cancer chemotherapy where there is a high possibility of
organ disfunction and possible other factors which are likely to affect pharmacokinetics
profile.
GLe and spectrophotometric methods were adapted for estimation of drug concentrations as
appropriate. Although highly sensitive analytical techniques such as mass-spectrometry have
been developed during the last decades, these methods are of limited practical value in drug
monitoring because of cost. Radiolabelled assays were not used because drugs, as used in
therapy, are not radiolabelled.
The results of the study showed that pharmacokinetic parameters of antipyrine in the normal
Kenyan Africans do not differ significantly from those that have been reported in caucasians.
On the other hand, the half-life of antipyrine was significantly prolonged and its total body
clearance markedly decreased in patients with Hodgkin's lymphoma. This suggests that
Hodgkin's lymphoma influences the disposition of some drugs via changes in
pathophysiology. Studies in patients with advanced liver disease showed that the half-life of
antipyrine was significantly increased and its total body clearance as well as hepatic
clearance was significantly decreased, although the apparent volume of distribution did not
differ significantly from that of controls.
Pharmacokinetic data obtained for pindolol was not significantly different from that reported
in the literature for caucasians. Pindolol alone did not lower the blood pressure of
hypertensive Kenyan Africans appreciably; however, the addition of a thiazide diuretic,
clopamide, improved its blood pressure lowering efficacy. It was concluded, therefore that
the poor response of hypertensive Africans to pindolol is not due to differences in
pharmacokinetics.
A study of the metabolism of cyclophosphamide showed that Africans did not metabolize
cyclophosphamide differently from Caucasians. However, the pharmacokinetics of
cyclophosphamide in severe liver disease revealed a significant change in half-life and total
body clearance suggesting that cyclophosphamide accumulates in the body in liver disease
and that its adverse effects would be expected to increase when liver function is
compromised. The high incidence of liver disease in Africa due schistosomal fibrosis and
hepatitisB is well known. Hepatoma is also known to be common in Africans. Awareness of
the pharmacokinetic effects of liver disease would therefore contribute to rational use of
drugs under these conditions.
In these studies computer simulations were used for estimation of pharmacokinetic
parameters. Student t-test and non-parametric tests were used for analysis of data.
Citation
Degree of Doctor of MedicinePublisher
University of Nairobi School of Medicine
Description
A thesis submitted in fulfillment for the Degree of
Doctor of Medicine in the University of Nairobi