RESUMEN
Nevirapine [NVP] is the first non-nucleoside reverse transcriptase inhibitor approved by the U.S. Food and Drug Administration [FDA] for use in combination therapy of HIV-1 infection. The favorable pharmacokinetic profile of NVP permits a simplified dosage and inexpensive regimen to prevent perinatal transmission, more especially in developing countries. Greater than 80% of administered NVP dose is transformed to glucuronidated conjugates of hydroxylated metabolites that are excreted in urine and only a small fraction of the dose [2.7%] was urinary excreted as the parent compound NVP. Adverse effects, mainly hypersensitivity skin reactions and hepatotoxicity, have emerged from NVP and hampered its use. Maculopapular rash and several cases of Stevens-Johnson syndrome have been reported in 17% of patients treated with NVP. 12-hydroxynevirapine has been proposed as a factor in nevirapine hepatocarcinogenicity and skin rashes. This work was conducted to explore the proposition that 12-hydroxy-NVP is the ultimate toxic metabolite responsible for the NVP induced side effects. Primary culture of skin fibroblasts of small female Brown Norway rats was utilized in this study, where the third and the fourth passaged cells were used. NVP, 12-hydroxy-NVP as well as 12-chloro-NVP [as surrogate for 12-hydroxy-NVP] were utilized for exploring the expression profiles of some genes as well as the cytotoxic potential of each of them. Also, the stability of 12-hydroxy and 12-chloro NVP in vitro was determined. Results showed that both of NVP and 12-hydroxy-NVP are free from any cytotoxic potential while 12-chloro-NVP exhibited cytotoxic effect in the third and the fourth passaged population. Each of NVP, 12-hydroxy-NVP or 12chloro-NVP caused some what similar gene expression profile. The stability study showed clear transformation of 12-chloro-NVP to more stable metabolite which is 12-hydroxy-NVP. As a conclusion obtained from the present work is that the main metabolite of NVP which is 12-hydroxy-NVP may not be the ultimate toxic metabolite responsible for NVP induced side effect. It is possible to propose that; 12-hydroxy-NVP may be further converted to ultra short lived ultimate toxic metabolite responsible for the adverse side effects. This suggested proposal need to be verified by more extensive and advanced works