title: 1-Aminobenzotriazole modulates oral drug pharmacokinetics through cytochrome P450 inhibition and delay of gastric emptying in rats.
abstract: 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.
authors.affiliation: 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.) rowan.stringer@novartis.com.
authors.forename: Rowan A
authors.initials: RA
authors.lastname: Stringer
authors.affiliation: 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.).
authors.forename: Eckhard
authors.initials: E
authors.lastname: Weber
authors.affiliation: 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.).
authors.forename: Bruno
authors.initials: B
authors.lastname: Tigani
authors.affiliation: 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.).
authors.forename: Paul
authors.initials: P
authors.lastname: Lavan
authors.affiliation: 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.).
authors.forename: Stephen
authors.initials: S
authors.lastname: Medhurst
authors.affiliation: 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.).
authors.forename: Bindi
authors.initials: B
authors.lastname: Sohal
mesh_terms: D000284:Administration, Oral; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D014230:Triazoles; C033020:1-aminobenzotriazole