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  • Species differences and substrate specificity of CYP3A heteroactivation by efavirenz.

Species differences and substrate specificity of CYP3A heteroactivation by efavirenz.

Xenobiotica; the fate of foreign compounds in biological systems (2014-11-12)
Yohei Kosugi, Junzo Takahashi
ABSTRACT

1. The purpose of this study was to clarify species differences in the heteroactivation of CYP3A substrates by efavirenz, which is known from clinical studies to activate midazolam 1'-hydroxylation, and to assess the feasibility of an animal model. 2. In monkey and human liver microsomes, efavirenz activated CYP3A-mediated midazolam 1'-hydroxylation, but had no effect in rat liver microsomes. The activating effect of efavirenz was also observed with recombinant human CYP3A4 and CYP3A5. Midazolam 4-hydroxylation, testosterone 6β-hydroxylation and the oxidation of nifedipine were not activated by efavirenz in any of the microsomes. 3. In an in vivo study using monkeys, the AUC ratio of midazolam/1'-hydroxymidazolam was reduced from 0.85 to 0.30 by efavirenz treatment, which was comparable to that obtained in clinical studies. However, the AUC changes of midazolam caused by efavirenz were smaller than those observed in clinical results, therefore the effect of efavirenz on monkeys was not completely consistent with that seen in humans. 4. In conclusion, this is the first report that efavirenz specifically activates midazolam 1'-hydroxylation only in monkey and human liver microsomes, revealing marked species differences and high substrate specificity in the heteroactivation. A further study is required to clarify whether this in vitro result reflects the in vivo situation.

MATERIALS
Product Number
Brand
Product Description

Diclofenac for system suitability, European Pharmacopoeia (EP) Reference Standard
Testosterone, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Oxidized Nifedipine, powder, ~95% (HPLC)
Supelco
Nifedipine, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
4-Hydroxymidazolam
Supelco
Diclofenac sodium salt, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Diclofenac sodium salt, analytical standard
Sigma-Aldrich
Diclofenac sodium salt
Sigma-Aldrich
Nifedipine, ≥98% (HPLC), powder
Sigma-Aldrich
Testosterone, purum, ≥99.0% (HPLC)
USP
Nifedipine Nitrophenylpyridine Analog, United States Pharmacopeia (USP) Reference Standard
Nifedipine, European Pharmacopoeia (EP) Reference Standard
USP
Nifedipine, United States Pharmacopeia (USP) Reference Standard
Diclofenac sodium, European Pharmacopoeia (EP) Reference Standard
Nifedipine impurity A, European Pharmacopoeia (EP) Reference Standard
USP
Diclofenac sodium, United States Pharmacopeia (USP) Reference Standard
Sigma-Aldrich
Efavirenz, ≥98% (HPLC)