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Utility of food pellets containing 1-aminobenzotriazole for longer term in vivo inhibition of cytochrome P450 in mice

Stringer, Rowan and Cordier, Valerie and Afatsawo, Catherine and Arabin, Philip and Desrayaud, Sandrine and Hoffmann, Laurent and Lehmann, Daniel and Lowe, Phil and Risser, Francis and Thiel, Julia and Widmer, Toni and 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

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