Stringer Rowan A, Williams Gareth, Picard Franck, Sohal Bindi, Kretz Olivier, McKenna Jeff, Krauser Joel A
Novartis Institutes for Biomedical Research, Horsham, West Sussex, UK (R.A.S., G.W., B.S., J.M.); and Novartis Pharma AG, Novartis Institutes for Biomedical Research, Drug Metabolism and Pharmacokinetics, Basel, Switzerland (F.P., O.K., J.A.K.).
Drug Metab Dispos. 2014 May;42(5):954-62. doi: 10.1124/dmd.114.057265. Epub 2014 Mar 10.
Deuterium isotope effects were evaluated as a strategy to optimize the pharmacokinetics of 7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo[5,1-b]oxazole (NVS-CRF38), a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist. In an attempt to suppress O-demethylation of NVS-CRF38 without losing activity against the CRF1 receptor, the protons at the site of metabolism were replaced with deuterium. For in vitro and in vivo studies, intrinsic primary isotope effects (KH/KD) were determined by the ratio of intrinsic clearance (CLint) obtained for NVS-CRF38 and deuterated NVS-CRF38. In vitro kinetic isotope effects (KH/KD) were more pronounced when CLint values were calculated based on the rate of formation of the O-desmethyl metabolite (KH/KD ∼7) compared with the substrate depletion method (KH/KD ∼2). In vivo isotope effects were measured in rats after intravenous (1 mg/kg) and oral (10 mg/kg) administration. For both administration routes, isotope effects calculated from in vivo CLint corresponding to all biotransformation pathways were lower (KH/KD ∼2) compared with CLint values calculated from the O-demethylation reaction alone (KH/KD ∼7). Comparative metabolite identification studies were undertaken using rat and human microsomes to explore the potential for metabolic switching. As expected, a marked reduction of the O-demethylated metabolite was observed for NVS-CRF38; however, levels of NVS-CRF38's other metabolites increased, compensating to some extent for the isotope effect.
氘同位素效应被评估为一种优化新型促肾上腺皮质激素释放因子受体1（CRF1）拮抗剂7-(3,5-二甲基-1H-1,2,4-三唑-1-基)-3-(4-甲氧基-2-甲基苯基)-2,6-二甲基吡唑并[5,1-b]恶唑（NVS-CRF38）药代动力学的策略。为了在不丧失对CRF1受体活性的情况下抑制NVS-CRF38的O-去甲基化，代谢位点的质子被氘取代。对于体外和体内研究，固有一级同位素效应（KH/KD）通过NVS-CRF38和氘代NVS-CRF38的固有清除率（CLint）之比来确定。与底物消耗法（KH/KD ∼2）相比，当根据O-去甲基代谢物的形成速率计算CLint值时，体外动力学同位素效应（KH/KD）更显著（KH/KD ∼7）。在大鼠静脉注射（1 mg/kg）和口服（10 mg/kg）给药后测量体内同位素效应。对于这两种给药途径，与仅根据O-去甲基化反应计算的CLint值（KH/KD ∼7）相比，由对应于所有生物转化途径的体内CLint计算的同位素效应更低（KH/KD ∼2）。使用大鼠和人微粒体进行了比较代谢物鉴定研究，以探索代谢转换的可能性。正如预期的那样，观察到NVS-CRF38的O-去甲基化代谢物显著减少；然而，NVS-CRF38其他代谢物的水平增加，在一定程度上补偿了同位素效应。
