Stringer Rowan A, Weber Eckhard, Tigani Bruno, Lavan Paul, Medhurst Stephen, Sohal Bindi
Novartis Institutes for Biomedical Research, Horsham, West Sussex, United Kingdom (R.A.S., E.W., P.L., S.M., B.S.); and Global Imaging Group, Novartis Pharma AG, Basel, Switzerland (B.T.)
Novartis Institutes for Biomedical Research, Horsham, West Sussex, United Kingdom (R.A.S., E.W., P.L., S.M., B.S.); and Global Imaging Group, Novartis Pharma AG, Basel, Switzerland (B.T.).
Drug Metab Dispos. 2014 Jul;42(7):1117-24. doi: 10.1124/dmd.113.056408. Epub 2014 Apr 11.
The simultaneous effects of the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) on inhibition of in vivo metabolism and gastric emptying were evaluated with the test compound 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 with low water solubility, and the reference compound midazolam with high water solubility in rats. Pretreatment of rats with 100 mg/kg oral ABT administered 2 hours before a semisolid caloric test meal markedly delayed gastric emptying. ABT increased stomach weights by 2-fold; this is likely attributable to a prosecretory effect because stomach concentrations of bilirubin were comparable in ABT and control groups. ABT administration decreased the initial systemic exposure of orally administered NVS-CRF38 and increased Tmax 40-fold, suggesting gastric retention and delayed oral absorption. ABT increased the initial systemic exposure of midazolam, however for orally (but not subcutaneously) administered midazolam, extensive variability in plasma-concentration time profiles was apparent. Careful selection of administration routes is recommended for ABT use in vivo, variable oral absorption of coadministered compounds can be expected due to a disturbance of gastrointestinal transit.
用受试化合物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-CRF38，一种新型的促肾上腺皮质激素释放因子受体1（CRF1）拮抗剂，水溶性低）和参考化合物咪达唑仑（在大鼠中水溶性高），评估细胞色素P450抑制剂1-氨基苯并三唑（ABT）对体内代谢抑制和胃排空的同时影响。在半固体热量测试餐2小时前给大鼠口服100mg/kg ABT进行预处理，显著延迟了胃排空。ABT使胃重量增加了2倍；这可能归因于促分泌作用，因为ABT组和对照组胃内胆红素浓度相当。给予ABT降低了口服NVS-CRF38的初始全身暴露，并使达峰时间增加了40倍，表明胃潴留和口服吸收延迟。ABT增加了咪达唑仑的初始全身暴露，然而对于口服（而非皮下）给予的咪达唑仑，血浆浓度-时间曲线存在明显的广泛变异性。建议在体内使用ABT时仔细选择给药途径，由于胃肠转运受到干扰，预计同时给予的化合物口服吸收会有变化。
