The metabolism of antiparasitic drugs and pharmacogenetics in African populations: From molecular mechanisms to clinical applications

Abstract

We characterised over 20 antiparasitic drugs with respect to the enzymes responsible for their metabolism. We showed that CYP2C8 is responsible for the metabolism of amodiaquine (ADQ) to desethylamodiaquine and identified a novel reactive metabolite catalysed by extrahepatic CYP1A1 and CYPIB1 which is giving us insights into possible ways of synthesising safer analogues of ADQ. Praziquantel (PZQ) was shown to be metabolised by CYP1A2 and 3A4, knowledge which is being used to explore the possibility of coadministering PZQ with known inhibitors of these enzymes in order to increase its bioavailability. From evaluating over 30 antiparasitic drugs for inhibition of major drug metabolising enzymes, 10 were shown to be potent inhibitors with a potential risk to cause metabolism based drug-drug interactions. The inhibitory effects of artemisinin and thiabendazole on CYP1A2 where further investigated in vivo and the effect of thiabedazole resulted in clinically relevant drug-drug interactions. We studied the genetic polymorphism of drug metabolising enzymes in African populations. We screened genes of 8 drug metabolising enzymes (CYP2B6, 2C9, 2C19, 2D6, FMO, NAT-2, GSTT and GSTM) for over 15 single nucleotide polymorphisms (SNPs) in 9 ethnic groups from across Africa (Ibo, Hausa and Yoruba of Nigeria, Luo, Kikuyu and Masai of Kenya, mixed Bantu volunteers from Tanzania, the Venda of South Africa, the Shona and San of Zimbabwe). Multivariate cluster analysis showed that Caucausian, Oriental and African populations show differential cluster groups, an indication that these major population groups are likely to metabolically handle medicines differently. Further studies led to the discovery of new genetic variants unique to populations of African origin such as CYP2D6∗17. Clinical studies on the metabolism and elimination of efavirenz by the polymorphic CYP2B6 showed that African populations had a reduced capacity to dispose efavirenz and that patients homozygous for the CYP2B6∗6 variant would require as low as half the dose given to Europeans to achieve the same safe and efficacious concentrations.