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Application of osmotic pumps for sustained release of 1-aminobenzotriazole and inhibition of cytochrome P450 enzymes in mice: Model comparison with the hepatic P450 reductase null mouse

Stringer, Rowan and Rose, Jonathan and Ferreira, Suzie and Ronseaux, Sebastien (2016) Application of osmotic pumps for sustained release of 1-aminobenzotriazole and inhibition of cytochrome P450 enzymes in mice: Model comparison with the hepatic P450 reductase null mouse. Drug Metabolism and Disposition, 44 (8). pp. 1213-1216. ISSN 0090-9556; 1521-009X

Abstract

The effectiveness of controlled release 1-aminobenzotriazole (ABT) administration to inhibit cytochrome P450 (P450) enzymes has been evaluated in mice. To maximize the duration of P450 inhibition in vivo, ABT was administered via an osmotic pump. The degree of P450 inhibition was compared with that achieved with a single bolus dose of ABT. Two-hour prior subcutaneous treatment of mice with ABT (50 mg/kg) inhibited antipyrine clearance by 88%. A less pronounced inhibitory effect (29% reduction in clearance) was observed when ABT was administered 24-hours before antipyrine administration, indicating partial restoration of P450 activity during this longer pretreatment time. The duration of ABT in mice was very short (mean residence time = 1.7 hours) after subcutaneous bolus administration. When the inhibitor was delivered by an osmotic pump, maximum blood concentrations of the inhibitor were observed 24 hours after device implantation and were maintained at steady state for 6 days. Inhibition of P450 activity, as measured by antipyrine clearance, was confirmed at 24 hours and 120 hours after pump implantation, highlighting the utility of this method as a longer-term model for P450 inhibition in mice. The magnitude of P450 inhibition in ABT-treated mice was compared with that in hepatic P450 reductase null mice and both models were comparable. In vivo ABT administration by an osmotic pump offers an effective approach for longer-term P450 inhibition in mice and avoids the necessity for multiple dosing of the inhibitor.

Item Type: Article
Additional Information: Unmapped bibliographic data: LA - English [Field not mapped to EPrints] ST - Application of osmotic pumps for sustained release of 1-aminobenzotriazole and inhibition of cytochrome P450 enzymes in mice: Model comparison with the hepatic P450 reductase null mouse [Field not mapped to EPrints] AU - Stringer, R. A. [Field not mapped to EPrints] AU - Ferreira, S. [Field not mapped to EPrints] AU - Rose, J. [Field not mapped to EPrints] AU - Ronseaux, S. [Field not mapped to EPrints] AD - (Stringer) Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel 4002, Switzerland [Field not mapped to EPrints] DB - Embase [Field not mapped to EPrints] DP - Ovid Technologies [Field not mapped to EPrints] AN - 20160518261 [Field not mapped to EPrints]
Keywords: animal experiment, 1 aminobenzotriazole/cr [Drug Concentration] , 1 aminobenzotriazole/pr [Pharmaceutics] , 1 aminobenzotriazole/pk [Pharmacokinetics] , 1 aminobenzotriazole/sc [Subcutaneous Drug Administration]
Date Deposited: 05 Jan 2017 00:45
Last Modified: 05 Jan 2017 00:45
URI: https://oak.novartis.com/id/eprint/28269

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