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.
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.
Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland (R.A.S); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (S.F., S.R.); and Novartis Institutes for Biomedical Research, Horsham, West Sussex, United Kingdom (J.R.) rowan.stringer@novartis.com.
Rowan A
RA
Stringer
Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland (R.A.S); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (S.F., S.R.); and Novartis Institutes for Biomedical Research, Horsham, West Sussex, United Kingdom (J.R.).
Suzie
S
Ferreira
Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland (R.A.S); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (S.F., S.R.); and Novartis Institutes for Biomedical Research, Horsham, West Sussex, United Kingdom (J.R.).
Jonathan
J
Rose
Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland (R.A.S); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (S.F., S.R.); and Novartis Institutes for Biomedical Research, Horsham, West Sussex, United Kingdom (J.R.).
Sebastien
S
Ronseaux
D000818:Animals; D000983:Antipyrine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000008:administration & dosage* / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency* / Q000235:genetics; D005838:Genotype; D015918:Infusion Pumps, Implantable; D055104:Infusions, Subcutaneous; D007279:Injections, Subcutaneous; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D018345:Mice, Knockout; D009997:Osmotic Pressure; D010641:Phenotype; D014230:Triazoles / Q000008:administration & dosage* / Q000097:blood
D065607:Cytochrome P-450 Enzyme Inhibitors; D014230:Triazoles; C033020:1-aminobenzotriazole; D003577:Cytochrome P-450 Enzyme System; D000983:Antipyrine