The role of CYP3A in nevirapine induced hepatotoxicity

[摘要] Nevirapine is a potent non-nucleoside reverse transcriptase inhibitor with favourablepharmacokinetics that are characterised by rapid absorption and distribution with along elimination half-life. Nevirapine is effective against HIV-1 when used incombination with other anti-retroviral agents and as a monotherapy for the preventionof mother-to-child-transmission. Unfortunately, its adverse effects, mainlyhypersensitivity skin reactions and hepatotoxicity, hamper the wide use of nevirapine.Since nevirapine-induced hepatotoxicity commonly occurs between 2 -12 weeks oftreatment, and nevirapine is a known inducer of CYP3A isozyme, it was envisagedthat the hepatotoxicity was due to activation of nevirapine to toxic metabolites by theinduced enzyme. Therefore, the aim of this study was to determine the role ofCYP3A in nevirapine-induced hepatotoxicity. Fifteen male SO rats were pre-treated with either dexamethasone (50 mg/kg) ornevirapine (20 mg/kg) for 3 days. On the fourth day, the control group (n=5) wasadministered with the vehicle, while the 'nevirapine only' group (n = 5) was given anoverdose of nevirapine (1340 mg/kg, orally) and the 'ketoconazole plus nevirapine'group (n = 5) was treated with a CYP3A inhibitor (ketoconazole) 1 hour before theoverdose of nevirapine was given. The animals were sacrificed 24 hrs later andplasma was sent for liver function tests, the liver was excised for microsomalextraction and histopathology studies. Microsomal CYP3A activity was measuredusing the erythromycin demethylation test. Results of these animals were comparedwith results obtained in rats that were not pre-treated with an inducer before the toxicdose of nevirapine was administered. Treatment with dexamethasone or nevirapine lead to increased CYP3A activity.CYP3A activity in the untreated, dexamethasone treated and nevirapine treated ratswas 0.59 ± OA8, 10.39 ± 3.59 and 7.28 ± 2.65 nmol/min/mg protein, respectively. Inthe dexamethasone pre-treated groups, the histopathological findings as well as theelevated liver enzymes of the 'nevirapine only' treated group (AST 239.25 ± 50.7 UILand ALT ± 386.00 ± 154.3 UIL) were indicative of hepatotoxicity as opposed to thecontrol group (AST 146AO ± 10A UIL and ALT 149.60 ± 39.7 UIL). However, the corresponding group pre-treated with nevirapine did not show significant elevations inliver enzymes (AST 150.20 ± 19.1 UIL and ALT 67.20 ± 8.6 UIL) but thehistopathological findings exhibited hepatotoxicity that was similar to thedexamethasone group. Nevirapine-induced hepatotoxicity was not prevented in thegroups treated with ketoconazole before the overdose of nevirapine was given.Interestingly, there was no hepatotoxicity when the overdose of nevirapine wasadministered to animals that were not pre-treated with nevirapine or dexamethasone.In conclusion, nevirapine-induced hepatotoxicity was associated with enzymeinduction by dexamethasone or nevirapine, and the use of ketoconazole did notprevent the hepatotoxicity. Therefore, CYP3A may not be involved in thepathogenesis of nevirapine-induced hepatotoxicity, suggesting that a differentenzyme may be responsible. As the liver function tests did not correlate well with thehistopathological findings in the nevirapine pre-treated groups, it was suggested thatliver function tests alone might not be good markers for determining nevirapineinducedhepatotoxicity.

[发布机构] University of the Free State