| Autor: |
Heck CJS; Department of Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States., Seneviratne HK; Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States., Bumpus NN; Department of Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States.; Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States. |
| Abstrakt: |
Cytochrome P450-dependent metabolism of the anti-HIV drug nevirapine (NVP) to 12-hydroxy-NVP (12-OHNVP) has been implicated in NVP toxicities. We investigated the impact of twelfth-position trideuteration (12-D 3 NVP) on the hepatic metabolism of and response to NVP. Formation of 12-OHNVP decreased in human (10.6-fold) and mouse (4.6-fold) hepatocytes incubated with 10 μM 12-D 3 NVP vs NVP. An observed kinetic isotope effect of 10.1 was measured in human liver microsomes. During mouse hepatocyte treatment (400 μM) with NVP or 12-D 3 NVP, cell death was reduced 30% with 12-D 3 NVP vs NVP, while glucuronidated and glutathione-conjugated metabolites increased with 12-D 3 NVP vs NVP. Using mass spectrometry proteomics, changes in hepatocyte protein expression, including an increase in stress marker insulin-like growth factor-binding protein 1 (IGFBP-1), were observed with 12-D 3 NVP vs NVP. These results demonstrate that while deuteration can reduce P450 metabolite formation, impacts on phase II metabolism and hepatocyte protein expression should be considered when employing deuteration to reduce P450 metabolite-related hepatotoxicity. |
