Artemisinin induces omeprazole metabolism in human beings.

OBJECTIVE: This study investigated whether time-dependent artemisinin pharmacokinetics correlated to CYP3A4 or CYP2C19 activity in vivo. METHODS: Artemisinin (two oral doses per day of 250 mg) was given to nine healthy Vietnamese subjects for 7 days (day 1 to day 7). Single 20 mg doses of omeprazole were given orally on day -7, day 1, and day 7. Single doses of artemisinin and omeprazole were given in combination on day 14 after a 6-day washout period. The pharmacokinetics of artemisinin, omeprazole, hydroxyomeprazole, and omeprazole sulfone were evaluated on days -7, 1, 7, and 14. On the same days urine was collected for the determination of 6beta-hydroxycortisol and cortisol excretion. RESULTS: Areas under plasma concentration-time curves (AUC) for artemisinin and omeprazole decreased on day 7 to 20% (95% confidence intervals, 13%, 28%) and 35% (25%, 46%), respectively, compared with values on day 1. AUC ratios for hydroxyomeprazole/omeprazole increased 2.2-fold (1.7, 2.7) on day 7 compared with values on day 1. All values were normalized at day 14. There were no significant changes in the omeprazole sulfone/omeprazole ratio or in the 6beta-hydroxycortisol/cortisol ratio between the study days. In one subject found to have poor CYP2C19 metabolization, the elimination of omeprazole increased after artemisinin exposure, with no change in the hydroxyomeprazole/omeprazole AUC ratio. CONCLUSION: Artemisinin did not alter CYP3A4 activity, whereas an increase in CYP2C19 activity was observed. The increased elimination of omeprazole in both poor and extensive CYP2C19 metabolizers suggests artemisinin induces both CYP2C19 and another enzyme.

Artemisinin pharmacokinetics in healthy adults after 250, 500 and 1000 mg single oral doses.

Eight healthy male, Vietnamese subjects were administered 1 x 250, 2 x 250, and 4 x 250 mg artemisinin capsules in a cross-over design with randomized sequence with a 7-day washout period between administrations. The inter-individual variability in artemisinin pharmacokinetics was large with parameter coefficient of variation (CV) typically between 50-70%. The parameter with the smallest variability was the elimination half-life (CV approximately equal to 30-40%). Analysis of variance indicated also a large intra-subject variability. (CV, or = 24%) for the dose-normalized area under the plasma concentration-time curve (AUC/dose). The pharmacokinetic results suggested artemisinin to be subject to high pre-systemic extraction. Artemisinin half-life could not predict the extent of in vivo exposure to the drug, there being no correlation between half-life and oral clearance. Artemisinin oral plasma clearance was about 400 L h-1 exhibiting a slight decrease with dose, although the effect was weak. Thus results from studies using different artemisinin doses may, within the studied dose range, be compared without the complication of disproportionate changes in drug exposure with varying dose levels. Half-lives appeared to increase with dose. An observed period effect in the analysis of variance was tentatively associated with time-dependency in artemisinin pharmacokinetics. There was a high correlation between artemisinin plasma concentrations determined at various time-points after drug administration and the AUCs after the 500 and 1000 mg doses, but less so after the 250 mg dose. This may show a tentative approach to assess the systemic exposure of the patients to artemisinin from the determination of artemisinin plasma concentrations in one or two plasma samples only. Artemisinin was well tolerated with no apparent dose or time dependent effects on blood pressure, heart rate or body temperature.

Artemisinin kinetics and dynamics during oral and rectal treatment of uncomplicated malaria.

OBJECTIVE: To compare parasite clearance times after oral and rectal administration of artemisinin in adults with uncomplicated malaria and to relate pharmacodynamics with artemisinin kinetics and to disclose any pharmacokinetic changes during treatment. METHODS: Thirty male Vietnamese patients with falciparum malaria were randomized to treatment with 500 mg artemisinin daily by either the oral or rectal route of administration. Parasite densities in capillary blood were determined by microscopy every 4 to 6 hours. Artemisinin plasma concentrations on the first and last day of treatment were determined by HPLC and unbound fractions in plasma were determined by ultrafiltration. RESULTS: Mean parasite clearance times and 95% confidence intervals (95% CI) were 25 (95% CI, 16 to 33) and 29 (95% CI, 23 to 35) hours during oral and rectal treatment, respectively. The bioavailability after rectal relative to oral artemisinin was 30%. Artemisinin areas under the plasma concentration-time curve (AUC) on the fifth (last) day of oral or rectal treatment were 30% (95% CI, 4% to 56%) and 40% (95% CI, -6% to 91%), respectively, of those after the first dose. The fraction unbound in plasma was 15% (95% CI, 12% to 19%), increasing marginally during treatment. No relationship was found between main clinical end points and drug exposure, although indices for the rapidity of response onset were lower after oral treatment and correlated to unbound AUC values (rS = -0.7; p < 0.001). CONCLUSIONS: The similarity in parasite clearance times despite lower drug levels during rectal treatment suggests that initial oral doses may be unnecessarily high. The singular time dependency of artemisinin pharmacokinetics, attributed to autoinduction of drug elimination, has possible implications for combination chemotherapy. Decreasing artemisinin concentrations during treatment may partly explain recrudescences and increase the risk for resistance development.