title: Effective dosing regimen of 1-aminobenzotriazole for inhibition of antipyrine clearance in guinea pigs and mice using serial sampling.
abstract: 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.
authors.affiliation: Millennium Pharmaceuticals, Inc., 45 Sidney Street, Cambridge, MA 02139, USA. suresh.balani@mpi.com
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Balani
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Joanne
authors.initials: J
authors.lastname: Nguyen
authors.forename: Kym
authors.initials: K
authors.lastname: Cardoza
authors.forename: Hang
authors.initials: H
authors.lastname: Zeng
authors.forename: Dun-Xue
authors.initials: DX
authors.lastname: Mu
authors.forename: Jing-Tao
authors.initials: JT
authors.lastname: Wu
authors.forename: Liang-Shang
authors.initials: LS
authors.lastname: Gan
authors.forename: Frank W
authors.initials: FW
authors.lastname: Lee
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000037:antagonists & inhibitors* / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D006168:Guinea Pigs; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D014230:Triazoles / Q000008:administration & dosage*
chemical_list: D014230:Triazoles; C033020:1-aminobenzotriazole; D000983:Antipyrine