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Detection of drug bioactivation in vivo: Mechanism of nevirapine-albumin conjugate formation in patients.

Chem Res Toxicol. 2013 Feb 28;

Authors: Meng X, Howarth A, Earnshaw CJ, Jenkins RE, French NS, Back DJ, Naisbitt DJ, Park BK


The non-nucleoside reverse transcriptase inhibitor nevirapine (NVP) is widely used for the treatment of human immunodeficiency virus type-1 (HIV-1), particularly in developing countries. Despite its therapeutic benefits, NVP has been associated with skin and liver injury in exposed patients. Although the mechanism of the tissue injury is not yet clear, it has been suggested that reactive metabolites of NVP may be involved. The detection of NVP mercapturate in the urine of patients undergoing standard antiretroviral chemotherapy indicates that NVP undergoes bioactivation in vivo. However, covalent binding of drug to protein in man remains to be determined. In the present study, we investigated the chemical basis of NVP protein adduct formation by using human serum albumin (HSA) and glutathione S-transferase Pi (GSTP) as model proteins in vitro. In addition, HSA was isolated from serum samples of HIV-1 patients undergoing NVP therapy to measure NVP haptenation in man. Mass spectrometric analysis of 12-sulfoxyl-NVP treated HSA revealed that the drug bound selectively to histidine (His146, His242 and His338) and a cysteine residue (Cys34). The reaction proceeds most likely by a concerted elimination/addition mechanism. This pathway was further confirmed by the observation of NVP-modified Cys47 in GSTP. Importantly, the same adduct (His146) was detected in HSA isolated from the blood of patients receiving NVP, providing direct evidence that NVP modifies protein in vivo, via the formation of a reactive metabolite.

PMID: 23448204 [PubMed - as supplied by publisher]