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Research ArticleArticle

1-Aminobenzotriazole Modulates Oral Drug Pharmacokinetics through Cytochrome P450 Inhibition and Delay of Gastric Emptying in Rats

Rowan A. Stringer, Eckhard Weber, Bruno Tigani, Paul Lavan, Stephen Medhurst and Bindi Sohal
Drug Metabolism and Disposition July 2014, 42 (7) 1117-1124; DOI: https://doi.org/10.1124/dmd.113.056408
Rowan A. Stringer
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.)
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Eckhard Weber
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.)
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Bruno Tigani
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.)
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Paul Lavan
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.)
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Stephen Medhurst
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.)
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Bindi Sohal
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.)
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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.

Footnotes

    • Received January 31, 2014.
    • Accepted April 11, 2014.
  • dx.doi.org/10.1124/dmd.113.056408.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (7)
Drug Metabolism and Disposition
Vol. 42, Issue 7
1 Jul 2014
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Research ArticleArticle

Inhibition of Gastric Emptying by ABT

Rowan A. Stringer, Eckhard Weber, Bruno Tigani, Paul Lavan, Stephen Medhurst and Bindi Sohal
Drug Metabolism and Disposition July 1, 2014, 42 (7) 1117-1124; DOI: https://doi.org/10.1124/dmd.113.056408

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Research ArticleArticle

Inhibition of Gastric Emptying by ABT

Rowan A. Stringer, Eckhard Weber, Bruno Tigani, Paul Lavan, Stephen Medhurst and Bindi Sohal
Drug Metabolism and Disposition July 1, 2014, 42 (7) 1117-1124; DOI: https://doi.org/10.1124/dmd.113.056408
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