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A model based assessment of the CYP2B6 and CYP2C19 inductive properties by artemisinin antimalarials: implications for combination regimens.

Journal article
Authors Doaa A Elsherbiny
Sara Asimus
Mats O Karlsson
Michael Ashton
Ulrika S H Simonsson
Published in Journal of pharmacokinetics and pharmacodynamics
Volume 35
Issue 2
Pages 203-17
ISSN 1567-567X
Publication year 2008
Published at Institute of Neuroscience and Physiology, Department of Pharmacology
Pages 203-17
Language en
Links dx.doi.org/10.1007/s10928-008-9084-...
Keywords Adult, Anticonvulsants, pharmacokinetics, Antimalarials, pharmacology, Artemisinins, pharmacology, Aryl Hydrocarbon Hydroxylases, biosynthesis, genetics, Biotransformation, Drug Combinations, Enzyme Induction, drug effects, Female, Genotype, Humans, Male, Mephenytoin, pharmacokinetics, Models, Statistical, Oxidoreductases, N-Demethylating, biosynthesis, genetics, Phenotype
Subject categories Pharmacy

Abstract

The study aim was to assess the inductive properties of artemisinin antimalarials using mephenytoin as a probe for CYP2B6 and CYP2C19 enzymatic activity. The population pharmacokinetics of S-mephenytoin and its metabolites S-nirvanol and S-4'-hydroxymephenytoin, including enzyme turn-over models for induction, were described by nonlinear mixed effects modeling. Rich data (8-16 samples/occasion/subject) were collected from 14 healthy volunteers who received mephenytoin before and during ten days of artemisinin administration. Sparse data (3 samples/occasion/subject) were collected from 74 healthy volunteers who received mephenytoin before, during and after five days administration of artemisinin, dihydroartemisinin, arteether, artemether or artesunate. The production rate of CYP2B6 was increased 79.7% by artemisinin, 61.5% by arteether, 76.1% by artemether, 19.9% by dihydroartemisinin and 16.9% by artesunate. The production rate of CYP2C19 increased 51.2% by artemisinin, 14.8% by arteether and 24.9% by artemether. In conclusion, all studied artemisinin derivatives induced CYP2B6. CYP2C19 induction by arteether and artemether as well as CYP2B6 and CYP2C19 induction by artemisinin was confirmed. The inductive capacity is different among the artemisinin drugs, which is of importance when selecting drugs to be used in antimalarial combination therapy such that the potential for drug-drug interactions is minimized.

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