In vitro evidence for auto-induction of artemisinin metabolism in the rat
| Autor: | Michael Ashton, Ulrika S H Svensson, S Gupta |
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| Rok vydání: | 2001 |
| Předmět: |
Male
Biology Pharmacology In Vitro Techniques Rats Sprague-Dawley Antimalarials Pharmacokinetics parasitic diseases medicine Animals Pharmacology (medical) Artemisinin Biotransformation Chromatography High Pressure Liquid Metabolism biology.organism_classification In vitro Artemisinins Rats Microsoma Toxicity Microsome Microsomes Liver Spectrophotometry Ultraviolet Sesquiterpenes Drug metabolism medicine.drug |
| Zdroj: | European journal of drug metabolism and pharmacokinetics. 26(3) |
| ISSN: | 0378-7966 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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