Artemisinin autoinduction is caused by involvement of cytochrome P450 2B6 but not 2C9.

AIM: Our goal was to investigate whether artemisinin autoinduction is caused by an increase in cytochrome P450 (CYP) 2B6 or CYP2C9 activities, we evaluated the effects of multiple-dose artemisinin administration on S-mephenytoin N-demethylation in healthy subjects. METHODS: Fourteen subjects, 6 poor metabolizers of CYP2C19 and 8 extensive metabolizers, received a single oral dose of 200 mg racemic mephenytoin (CYP2B6 in vivo marker) before (day -28) and during multiple-dose artemisinin administration (250 mg/d orally for 9 days and 500 mg on the tenth day). A 500-mg single dose of artemisinin was administered on day -28. The CYP2C9 in vivo marker tolbutamide was administered on day -28 and on days 7, 12, and 17 to monitor the minor involvement of CYP2C9 in S-mephenytoin N-demethylation. RESULTS: Artemisinin oral clearance increased 5.3-fold (P <.001) by the tenth day of administration. Its pharmacokinetics was not different in the 2 CYP2C19 phenotypes. The oral clearance of R-mephenytoin increased 1.7-fold (P <.05) in both phenotypes during the period of artemisinin administration. The area under the concentration-time curve ratio of S-nirvanol/S-mephenytoin, an index of CYP2B6 activity, increased 1.9-fold (P <.05) in CYP2C19 poor metabolizers during artemisinin multiple-dose administration, whereas the urinary excretion ratio of hydroxytolbutamide plus carboxytolbutamide/tolbutamide remained constant during the study period. CONCLUSIONS: These results indicate that artemisinin induces the N-demethylation of S-mephenytoin probably by an increased capacity of CYP2B6. The autoinduction phenomenon of artemisinin may, therefore, be attributed, at least in part, to induction of CYP2B6, because this is the isozyme primarily involved in its metabolism. In addition, artemisinin alters the disposition of R-mephenytoin by an unidentified isozyme.

Artemisinin pharmacokinetics and efficacy in uncomplicated-malaria patients treated with two different dosage regimens.

The immediate efficacies of two oral dosage regimens of artemisinin were investigated in 77 male and female adult Vietnamese falciparum malaria patients randomly assigned to treatment with either 500 mg of artemisinin daily for 5 days (group A; n = 40) or artemisinin at a dose of 100 mg per day for 2 days, with the dose increased to 250 mg per day for 2 consecutive days and with a final dose of 500 mg on the fifth day (group B; n = 37). Parasitemia was monitored every 4 h. The average parasite clearance time was longer in group B than in group A (means +/- standard deviations, 50 +/- 23 and 34 +/- 14 h, respectively; P < 0.01). Artemisinin concentrations in saliva samples obtained on days 1 and 5 were quantified by high-performance liquid chromatography. The average oral clearance, based on saliva drug concentrations in group B patients, was twofold higher than that in group A patients on day 1 (P < 0.01), with no differences in drug half-lives (P = 0.40), indicating a saturable first-pass metabolism. Female patients had higher oral clearance values on day 1. Artemisinin's pharmacokinetic parameters were similar on day 5 in both groups, although a significant increase in oral clearance from day 1 to day 5 was evident. Thus, artemisinin exhibited both dose- and time-dependent pharmacokinetics. The escalating dose studied did not result in higher artemisinin concentrations toward the end of the treatment period.