In vitro evidence for auto-induction of artemisinin metabolism in the rat
2001 (English)In: European journal of drug metabolism and pharmacokinetics, ISSN 0378-7966, Vol. 26, no 3, 173-178 p.Article in journal (Refereed) Published
Artemisinin disappearance rate was more rapid in incubations with liver microsomes from rats pre-treated with oral artemisinin (60 mg/kg/day for 5 days) compared with microsomes from control animals. A single pathway Michaelis-Menten saturable elimination model was fitted to the concentration-time data of artemisinin incubations by non-linear regression. Model parameters were obtained after fitting results for each animal separately and by pooling data for pre-treated and control animals. Parameter estimates (% coefficient of variation) from fitting the pooled data was maximum velocities (V-max) = 1.8 (12) mmole/min/mg protein and Michaelis constants (K-m) = 20 (22) muM for artemisinin pre-treated and V-max = 0.85 (35) mmole/min/mg protein and K-m = 67 (52) muM for control animals indicating a 2-fold increase in V-max and a 3-fold decrease in Km with microsomes from artemisinin pre-treated animals. Estimates of intrinsic clearance in microsomes from the pre-treated animals were 8-fold higher compared with controls. Thus, artemisinin appears to be a potent auto-inducer of drug metabolism in rats as has also been observed in humans. The present findings suggest caution in the interpretation of repeat-dose rat toxicity studies with artemisinin unless its pharmacokinetics are simultaneously monitored, since during multiple administration, the exposure of the drug will not be constant over time.
Place, publisher, year, edition, pages
2001. Vol. 26, no 3, 173-178 p.
artemisinin, rat liver microsomes, in vitro, pharmacokinetics
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-208923ISI: 000171803200005OAI: oai:DiVA.org:uu-208923DiVA: diva2:655500