1-Aminobenzotriazole modulates oral drug pharmacokinetics through cytochrome P450 inhibition and delay of gastric emptying in rats
| Autor: | Eckhard Weber, Bruno Tigani, Paul Lavan, Stephen J. Medhurst, Bindi Sohal, Rowan Stringer |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Pharmacology
Gastric emptying Chemistry Bilirubin Stomach Antagonist Pharmaceutical Science Administration Oral Absorption (skin) Triazoles Rats Rats Sprague-Dawley chemistry.chemical_compound medicine.anatomical_structure Pharmacokinetics Gastric Emptying In vivo medicine Midazolam Animals Cytochrome P-450 Enzyme Inhibitors Female Rats Wistar medicine.drug |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 42(7) |
| ISSN: | 1521-009X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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