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In vitro evidence for auto-induction of artemisinin metabolism in the rat.

Journal article
Authors S Gupta
U S Svensson
Michael Ashton
Published in European journal of drug metabolism and pharmacokinetics
Volume 26
Issue 3
Pages 173-8
ISSN 0378-7966
Publication year 2001
Published at Institute of Physiology and Pharmacology, Dept of Pharmacology
Pages 173-8
Language en
Links www.ncbi.nlm.nih.gov/entrez/query.f...
Keywords Animals, Antimalarials, pharmacokinetics, pharmacology, Artemisinins, Biotransformation, drug effects, Chromatography, High Pressure Liquid, Male, Microsomes, Liver, metabolism, Rats, Rats, Sprague-Dawley, Sesquiterpenes, pharmacokinetics, pharmacology, Spectrophotometry, Ultraviolet
Subject categories Pharmacy

Abstract

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 (Vmax) = 1.8 (12) mmole/min/mg protein and Michaelis constants (Km) = 20(22) microM for artemisinin pre-treated and Vmax = 0.85 (35) mmole/min/mg protein and Km = 67(52) microM for control animals indicating a 2-fold increase in Vmax 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.

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