Stringer, Rowan, Cordier, Valerie, Afatsawo, Catherine, Arabin, Philip, Desrayaud, Sandrine, Hoffmann, Laurent, Lehmann, Daniel, Lowe, Phil, Risser, Francis, Thiel, Julia, Widmer, Toni, Wipfli, Peter and Bigaud, Marc (2017) Utility of food pellets containing 1-aminobenzotriazole for longer term in vivo inhibition of cytochrome P450 in mice. Xenobiotica. ISSN 1366-5928; 0049-8254

Abstract

The utility of 1-aminobenzotriazole (ABT) incorporated in food pellets has been investigated as an approach for longer term in vivo inhibition of cytochrome P450 (P450) activity in mice. Drug-drug interaction studies were conducted between NVS-CRF38 and ABT to determine whether ABT delays gastric emptying in mice. 2-h oral treatment with 50 mg/kg ABT inhibited the oral absorption of NVS-CRF38 (Tmax was 4 hours for ABT treated mice compared to 0.5 hours in the control group), however the magnitude of the effect was less marked than previously observed in rats. A one month drug-drug interaction in mice was undertaken with ABT containing food pellets. Antipyrine, a non-isoform specific substrate of P450 enzymes, was administered by oral gavage on three occasions over the 1 month period. Marked inhibition of antipyrine oral clearance was observed at day 3 (88% of control), week 2 (83% of control) and week 4 (80% of control). The drug concentration-time profile for ABT was reliably predicted by a modelling a simulation approach based on the circadian feeding behaviour of mice, this model provides a useful tool when designing studies with drugs incorporated into food. The inclusion of ABT in food provides a minimally invasive and convenient approach to achieve longer term inhibition of in vivo P450 activity. This model can be used to enable pharmacological proof-of-concept studies for research compounds which are metabolized by P450 enzymes.

Item Type:	Article
Date Deposited:	28 Dec 2017 00:45
Last Modified:	28 Dec 2017 00:45
URI:	https://oak.novartis.com/id/eprint/33593