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-l blood samples were drawn from jugular veincannulated 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 M) 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 (K I ) for ABT as the P450 mechanism-based inactivator were determined to be 45.6 and 193 M, and the maximal inactivation rate constants (k inact ) 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 C max 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.In our last communication (Balani et al., 2002), the dosing regimen of 1-aminobenzotriazole (ABT), a nonspecific inhibitor of cytochromes P450 (P450s) (Huijzer et al., 1989;Constan et al., 1999), was established in rats, dogs, and monkeys to effectively inhibit P450s and hence decrease the plasma clearance and increase the exposure of antipyrine (AP), a nonspecific probe substrate of P450s (Engel et al., 1996;Sharer and Wrighton, 1996;Matzke et al., 2000). All P450s were shown to be affected by ABT treatment (Balani et al., 2002). Due to wide distribution of ABT in rats, P450 inhibition is expected to be general in the body tissues (Town et al., 1993). The literature previously contained varied treatment of animals with ABT (e.g., dosing route, dose level, pretreatment time, and frequency of dosing). The current study extends our previous studies to mice and guinea pigs, which are routinely used for mechanistic PK, toxicity, and pharmacology studies; thus, it is intended to provide guidelines for the pretreatment of animals with ABT to significantly alter the oxidative metabolism of test compounds (e.g., to evaluate metabolite versus parent compound-based toxicities or boost compound concentration available for a target enzyme or receptor). Although the safety assessment of chronic dosing of ABT in mice and guinea pigs has not been reported, its safety in rats has clearly been demonstrated (Mico et al., 1988). This report also highligh...
We compared the current antithrombotic strategy of antiplatelet therapy with aspirin, and anticoagulant therapy with heparin, with a specific genetically engineered chimeric antibody (c7E3 Fab) directed against the human glycoprotein IIb/IIIa receptor in an animal model of arterial thrombosis. Anesthetized cynomolgus monkeys (Macaca fascicularis) were instrumented for monitoring of arterial blood pressure, heart rate, and carotid artery flow velocity. Animals were treated with saline (n = 6), aspirin (25 mg PO daily for 3 days; n = 6), heparin (100 U/kg i.v. plus infusion adjusted to maintain activated partial thromboplastin time at 2 to 3 times baseline; n = 6), aspirin plus heparin (as administered separately, n = 6), or c7E3 Fab (0.10 mg/kg i.v., n = 7; 0.15 mg/kg i.v., n = 6; 0.20 mg/kg i.v., n = 6; 0.25 mg/kg i.v., n = 6). Thrombus formation via anodal electrolytic stimulation (100 microA) to the intimal surface of the right carotid artery was initiated 15 minutes after drug administration and continued for 180 minutes. Electrolytic injury to the left carotid artery began 210 minutes after drug administration and continued for 180 minutes. Whole blood cell counts, glycoprotein IIb/IIIa receptor blockade, ex vivo platelet aggregation, template bleeding time, and activated partial thromboplastin time were assessed at various time points throughout the experimental protocol. Hemodynamic and hematologic parameters were comparable among groups at baseline. Treatment with c7E3 Fab inhibited ex vivo platelet aggregation, increased bleeding time, decreased thrombus weight, and increased time to occlusion in a dose-dependent manner in both vessels. Treatment with aspirin, heparin, or the combination of aspirin plus heparin was ineffective for the prevention of carotid artery thrombosis in this model. Inhibition of the platelet glycoprotein IIb/IIIa receptor with c7E3 Fab was found to be safe and effective for the prevention of primary thrombus formation, whereas treatment with either aspirin or heparin or the combination of the two agents failed to protect against occlusive thrombus formation in cynomolgus monkeys.
Background and Purpose: The two objectives of this study were to assess the potential of BAY U 3405 to prevent arterial thrombosis in response to vessel wall injury and to determine the ability of BAY U 3405 to prevent thrombotic reocclusion after thrombolysis with anisoylated plasminogen streptokinase activator complex.Methods: Dogs were instrumented with a carotid flow probe, stimulating electrode, and a stenosis. Current (150 pA) was applied to the intimal surface of the right carotid artery, and time to occlusive thrombus formation was noted. BAY U 3405 was administered, and the procedure for thrombus formation was repeated for the left carotid artery.Results: BAY U 3405 administration prevented occlusive arterial thrombosis formation. Ex vivo platelet aggregation was inhibited, bleeding time increased, and thrombus weight reduced after BAY U 3405 treatment. In a second group, thrombi were formed initially in both carotid arteries, BAY U 3405 was administered as before, and anisoylated plasminogen streptokinase activator complex was infused in the right carotid artery proximal to the occlusive thrombus. BAY U 3405 did not alter the incidence of rethrombosis compared with the lytic agent alone.
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