Stringer, Rowan, Weber, Eckhard, Tigani, Bruno, Lavan, Paul, Stephen, Medhurst and Sohal, Bindi (2014) 1-aminobenzotriazole modulates oral drug pharmacokinetics through cytochrome P450 inhibition and delay of gastric emptying in rats. Drug Metabolism and Disposition, 42 (7). pp. 1117-1124. ISSN 1521-009X

Abstract

The simultaneous effect of the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) on inhibition of in vivo metabolism and gastric emptying was evaluated with the test compound NVS308, a novel CRF1 antagonist with low water solubility, and the reference compound midazolam with high water solubility in rats. Pre-treatment of rats with 100 mg/kg oral. ABT administered 2 hours prior to a semi-solid caloric test meal, markedly delayed gastric emptying. ABT increased stomach weights by 2-fold, this is likely to be attributed to a pro-secretory effect because stomach concentrations of bilirubin were comparable in ABT and control groups. ABT administration decreased the initial systemic exposure of orally administered NVS308 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 co-administered compounds can be expected due to a disturbance of gastrointestinal transit.

Item Type:	Article
Keywords:	Aminobenzotriazole, pharmacokinetic, cytochrome P450, drug metabolism, gastric emptying
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/9326