Investigation of a Metabolic Pathway Leading to an Idiosyncratic Drug Reaction: Is the Sulfate of 12-Hydroxynevirapine Responsible for the Skin Rash in Brown Norway rats?

• Main Author: Novalen, Maria
• Other Authors: Uetrecht, Jack
• Language: en_ca
• Published: 2010
• Subjects: nevirapine; drug metabolism; adverse drug reactions; idiosyncratic drug reactions; 0383
• Online Access: http://hdl.handle.net/1807/25882

An animal model of nevirapine (NVP)-induced skin rash was used to test the hypothesis that sulfonation of 12-OH NVP, a metabolite of NVP proven essential for rash development, is the link between 12-OH NVP and the skin rash. Female Brown Norway (BN) rats were co-treated with NVP or 12-OH NVP and sulfation inhibitors dehydroepiandrosterone (DHEA) and salicylamide. Co-treatment with salicylamide markedly decreased formation of the sulfate conjugate but did not prevent development of the rash suggesting that the sulfate is not involved. However, it is not known whether the sulfate formation in the skin was affected. Co-treatments with DHEA decreased the sulfate formation and prevented the rash but also had other effects on NVP metabolism. This implies that the sulfate metabolite is responsible for the rash. Additional studies will be required to resolve these conflicting results.