Demonstration of the metabolic pathway responsible for nevirapine-induced skin rash

Chemical Research in Toxicology
Jie ChenJack P Uetrecht

Abstract

The reverse transcriptase inhibitor, nevirapine (NVP), causes skin rashes and hepatotoxicity. We used a rat model to determine if the rash is caused by the parent drug or a reactive metabolite. By manipulation of metabolic pathways and testing analogues, we eliminated all but one pathway, 12-hydroxylation, which involves the oxidation of an exocyclic methyl group, as being responsible for the rash. Treatment with 12-OH-NVP caused a rash, and an analogue in which the methyl hydrogens were replaced by deuterium to inhibit the 12-OH pathway did not cause a rash; however, quite unexpectedly, blood levels of the deuterated analogue were very low. This is due to partitioning of the benzylic free radial intermediate between oxygen rebound to form 12-OH-NVP and loss of another hydrogen atom to form a reactive quinone methide, which inactivates P450. Cotreatment with the P450 inhibitor, 1-aminobenzotriazole, led to comparable levels of NVP and the deuterated analogue, and the deuterated analogue still caused a lower rash incidence. These data clearly point to the 12-hydroxy pathway being responsible for NVP skin rash. We propose that the hepatotoxicity of NVP in humans is due to the quinone methide formed by P450 in the liver, while the...Continue Reading

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Citations

Sep 3, 2010·Chemical Research in Toxicology·Alexandra M M AntunesM Matilde Marques
Oct 3, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Abhishek SrivastavaB Kevin Park
Mar 6, 2013·Antimicrobial Agents and Chemotherapy·Patty Fan-HavardUNKNOWN ANRS12154 Study Group
Nov 19, 2010·Drug Metabolism and Pharmacokinetics·Xiaochu ZhangJack Uetrecht
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Oct 30, 2013·Drug Metabolism Reviews·Amy M Sharma, Jack Uetrecht
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Dec 2, 2015·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Aline T MarinhoSofia A Pereira
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Apr 16, 2010·Chemical Research in Toxicology·Alexandra M M AntunesM Matilde Marques
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Feb 8, 2013·Chemical Research in Toxicology·Amy M SharmaJack Uetrecht
Apr 18, 2013·Chemical Research in Toxicology·Amy M SharmaJack P Uetrecht
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