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

Eur J Drug Metab Pharmacokinet. Jul-Sep 2001;26(3):173-8. doi: 10.1007/BF03190393.

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.

MeSH terms

  • Animals
  • Antimalarials / pharmacokinetics*
  • Antimalarials / pharmacology*
  • Artemisinins*
  • Biotransformation / drug effects
  • Chromatography, High Pressure Liquid
  • In Vitro Techniques
  • Male
  • Microsomes, Liver / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Sesquiterpenes / pharmacokinetics*
  • Sesquiterpenes / pharmacology*
  • Spectrophotometry, Ultraviolet

Substances

  • Antimalarials
  • Artemisinins
  • Sesquiterpenes
  • artemisinine