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Balani, S.K. et al.

Balani, Li, Nguyen, Cardoza, Zeng, Mu, Wu, Gan, Lee,

Effective dosing regimen of 1-aminobenzotriazole for inhibition of antipyrine clearance in guinea pigs and mice using serial sampling.

Single-dose pharmacokinetics of 1-aminobenzotriazole (ABT), a potent nonspecific inhibitor of cytochromes P450 (P450s), were characterized after oral administration to mice and guinea pigs at doses of 50, 100, and 150 mg/kg using serial sampling in both species. Only 30-microl blood samples were drawn from jugular vein-cannulated mice using Microvette capillary tubes containing lithium heparin. A comparison of the pharmacokinetics of antipyrine (AP) administered i.v. at 20 mg/kg to mice followed by serial and terminal sampling techniques yielded similar results. The ABT concentrations in plasma were sustained at high levels (5-100 microM) for at least 12 h in both species. Pretreatment of animals with ABT 2 h prior to AP administration decreased the plasma AP clearance by about 95% in mice at all ABT doses studied and 84, 95, and 95% in guinea pigs at a dose of 50, 100, and 150 mg/kg ABT, respectively. In vitro, the dissociation constants (KI) for ABT as the P450 mechanism-based inactivator were determined to be 45.6 and 193 microM, and the maximal inactivation rate constants (kinact) were determined to be 0.089 and 0.075 min(-1) for the mouse and guinea pig liver microsomes, respectively. The projected P450 inactivations at the plasma Cmax of ABT agreed with the inhibitions of P450-mediated AP clearance observed in vivo. For mechanistic studies in vivo overall, a 2-h prior oral pretreatment with ABT at 50 mg/kg in mice and 100 mg/kg in guinea pigs would provide significant systemic concentrations of the inhibitor over 24 h and inhibition of P450-dependent clearance of test compounds.[1]

References

Effective dosing regimen of 1-aminobenzotriazole for inhibition of antipyrine clearance in guinea pigs and mice using serial sampling. Balani, S.K., Li, P., Nguyen, J., Cardoza, K., Zeng, H., Mu, D.X., Wu, J.T., Gan, L.S., Lee, F.W. Drug Metab. Dispos. (2004) [Pubmed]

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