Effects of concurrent administration of efavirenz on the disposition kinetics of amodiaquine in healthy volunteers

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

“…Amodiaquine is rapidly and extensively metabolized by CYP2C8 to active desethylamodiaquine, which has a long half-life of 9-18 days. In healthy subjects, trimethoprim and efavirenz have been reported to increase the AUC of amodiaquine by 1.6-and 1.8-fold, respectively, and to reduce that of desethylamodiaquine by 12 and 26%, respectively (Soyinka et al, 2013;Akande et al, 2015). In an earlier study, efavirenz raised the AUC of amodiaquine in two healthy subjects by 2-to 4-fold and decreased the AUC of desethylamodiaquine by 24 and 8.5% (German et al, 2007).…”

CYP2B6 Genotype‐Dependent Inhibition of CYP1A2 and Induction of CYP2A6 by the Antiretroviral Drug Efavirenz in Healthy Volunteers

“…In contrast to the induction effects of efavirenz on gene expression, drug interactions also occur as a result of direct enzymatic inhibition by efavirenz . Our findings clearly indicate that chronic doses of efavirenz significantly reduced CYP1A2 activity in vivo compared with CYP1A2 activity determined when caffeine was administered with a single dose of efavirenz.…”

“…However, not all DDIs with efavirenz are due to induction of drug disposition genes. Our in vitro data show that efavirenz directly inhibits certain enzymes at therapeutically relevant concentrations (e.g., CYP2B6, CYP2C8, CYP2C19, and CYP2C9), with reduction in the elimination of CYP2C8 and CYP2C9 substrates in vivo and efavirenz being a mixed inhibitor/inducer of CYP2B6 and CYP2C19 . The potential in vivo effect of efavirenz on the activity of other drug metabolizing enzymes, such as CYP1A2, CYP2A6, xanthine oxidase (XO), and N‐acetyltransferase 2 (NAT2), is not fully investigated.…”