کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2512305 1118336 2014 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Investigating the contribution of CYP2J2 to ritonavir metabolism in vitro and in vivo
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی داروشناسی
پیش نمایش صفحه اول مقاله
Investigating the contribution of CYP2J2 to ritonavir metabolism in vitro and in vivo
چکیده انگلیسی

Ritonavir, an HIV protease inhibitor, is successfully used for the prevention and treatment of HIV infections. Ritonavir pharmacokinetics are complicated by inhibition, induction and pharmacogenetics of cytochrome P450 (CYP) enzymes mediating its clearance. This investigation revealed that CYP2J2, along with CYP3A4/5 and CYP2D6, efficiently metabolizes ritonavir, and to a CYP2J2-specific (minor) metabolite. Chemical inhibition of ritonavir metabolism, clearance, KI/kinact and abundance of CYP2J2 in liver microsomes were evaluated and then applied to an in vitro–in vivo static scaling model to estimate the contribution of each isozyme, as a function of CYP abundance, activity, and genotype. Disposition of the CYP2J2-specific metabolite was also evaluated in vivo. In plasma, metabolite abundance was well above previously reported levels with circulating concentrations measured at 2 μM for the main hydroxylisopropyl metabolite. Ritonavir and metabolite plasma profiles were simulated using Simcyp®. A modest (2–6%) contribution of CYP2J2 to ritonavir clearance is predicted which increases to more than 20% in subjects carrying CYP2D6 poor metabolizer polymorphisms and CYP3A4 irreversible inhibition. These results indicate that minor drug metabolizing enzymes could become quantitatively important in RTV clearance if main metabolic pathways are impeded.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 91, Issue 1, 1 September 2014, Pages 109–118
نویسندگان
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