Evaluation of metabolic stability of antimalarial and antiretroviral drugs

Abstract

The concomitant administration of drugs and antimalarial drugs is recommended for the treatment of HIV (Human Immunodeficiency Virus) patients with malaria resulting in drug-drug interactions (DDI) causing either lack of efficacy or toxicities. Drug metabolism is often the first step in understanding the DDI potential of either a new chemical entity or a combination of drugs. inhibitor (PI) such as is a potent CYP 3A4 inhibitor and may interact with these antimalarial drugs that are metabolized by CYP3A4 to cause metabolism-related DDI's. the present study is an attempt to evaluate the potential for a drug-drug interaction between and through metabolic stability studies. Metabolic stability of antimalarial and drugs alone and in combination with and without and was evaluated using human liver (HLM). The antimalarial drugs , and were metabolically unstable alone (% metabolism ≥ 80%) and in combination with other antimalarial drugs in HLM. , and were metabolically stable (% metabolism ≤ 30%). drug was metabolically unstable while was moderately stable. intrinsic clearance of antimalarial drugs , and decreased from 106.4, 290.6 and 230 ml/min/kg to 32, 44.8 and 49.5 ml/min/kg in the presence of . However, there was no change in the intrinsic clearance of , and in the presence of . did not alter the clearance of antimalarial drugs. This study suggests that affected the clearance of a few antimalarial drugs in HLM probably by the inhibition of CYP3A4 and findings may need to be further evaluated in clinical studies.