Effect of pretreatment regimens of 1-aminobenzotriazole on metabolism and gastric emptying of probe compounds in rat

Abstract

1. 1-Aminobenzotriazole (ABT) is a mechanism-based inactivator of major cytochrome P450 (CYP) enzymes, which is used in multiple mechanistic studies.

2. The purpose was to evaluate the effect of 2 and 16-h pretreatment regimens of ABT on the exposures of triazolam in rat. Another objective was to evaluate the effect of ABT on gastric emptying of acetaminophen.

3. Plasma area under the curve (AUC) of triazolam was increased by 101-fold and 81-fold for the rats pretreated with ABT at 2 and 16 h, respectively, compared to control rats. Time to reach maximum concentration was 0.3, 4.8 and 3.7 h in control, 2 and 16-h pretreatment animals, respectively. In the case of acetaminophen, where T_max was not delayed, the mean absorption time (MAT) in control, 2 and 16 h ABT pretreatment groups were 0.3, 4.6 and 2.9 h, respectively, suggesting delayed absorption. This hypothesis was further supported by GastroPlus^TM simulation.

4. In summary, extent of triazolam absorption was increased to a similar extent with both 2 and 16 h ABT pretreatment regimens, suggesting that either of the regimen can be used to increase parent exposures in rat. With ABT pretreatment, delayed absorption of triazolam and acetaminophen was observed, as suggested by delay in T_max and MAT, respectively.

Keywords:

• Aminobenzotriazole
• triazolam
• acetaminophen
• gastric emptying
• metabolism
• pharmacokinetic studies

Acknowledgements

The authors would like to thank Punit Marathe, Kimberley Lentz and Mike Sinz for their support and helpful discussions.

Disclosure statement

No potential conflict of interest was reported by the authors.