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.