Distribution of 1-aminobenzotriazole in male rats after administration of an oral dose

Town, Christopher; Henderson, L; Chang, Ding; Mortillo, Mildred; Garland, William A.

doi:10.3109/00498259309057026

Cited by 18 publications

(20 citation statements)

References 6 publications

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“…We considered the hypothesis that ABT inhibits gastric emptying in the rat, thus delaying absorption of NVS-CRF38. Some evidence of ABT-induced retention of stomach contents has been reported, Town's study reveals that ;50% of 14 C-ABT remains in the stomachs of rats 6 hours after oral administration (Town et al, 1993). Our gastric emptying studies, using a noninvasive technology (Gremlich et al, 2004), demonstrate that ABT inhibits gastric emptying in rats.…”

Section: Discussionmentioning

confidence: 67%

1-Aminobenzotriazole Modulates Oral Drug Pharmacokinetics through Cytochrome P450 Inhibition and Delay of Gastric Emptying in Rats

et al. 2014

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The simultaneous effects of the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) on inhibition of in vivo metabolism and gastric emptying were evaluated with the test compound 7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo [5,1-b]oxazole(NVS-CRF38), a novel corticotropin releasing factor receptor 1 (CRF 1 ) antagonist with low water solubility, and the reference compound midazolam with high water solubility in rats. Pretreatment of rats with 100 mg/kg oral ABT administered 2 hours before a semisolid caloric test meal markedly delayed gastric emptying. ABT increased stomach weights by 2-fold; this is likely attributable to a prosecretory effect because stomach concentrations of bilirubin were comparable in ABT and control groups. ABT administration decreased the initial systemic exposure of orally administered NVS-CRF38 and increased T max 40-fold, suggesting gastric retention and delayed oral absorption. ABT increased the initial systemic exposure of midazolam, however for orally (but not subcutaneously) administered midazolam, extensive variability in plasma-concentration time profiles was apparent. Careful selection of administration routes is recommended for ABT use in vivo, variable oral absorption of coadministered compounds can be expected due to a disturbance of gastrointestinal transit.

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Section: Discussionmentioning

confidence: 67%

1-Aminobenzotriazole Modulates Oral Drug Pharmacokinetics through Cytochrome P450 Inhibition and Delay of Gastric Emptying in Rats

et al. 2014

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“…Other enzymes, like NADPH cytochrome c reductase, glutathione S-transferase, and glucuronyl transferase are not affected by this inhibitor (Mugford et al, 1992), and hence ABT is a fairly selective P450 inhibitor. [ 14 C]ABT is known to be well absorbed (Ն70%) in rats and radioactivity distributed widely throughout the body, with liver, kidney, and adrenals showing the highest levels (Town et al, 1993). Thus, the inhibition of P450s is expected in many organs.…”

Section: Resultsmentioning

confidence: 99%

“…14 C]ABT is known to be well absorbed (Ն70%) in rats and radioactivity distributed widely throughout the body, with liver, kidney, and adrenals showing the highest levels (Town et al, 1993). Thus, the inhibition of P450s is expected in many organs.…”

Section: Resultsmentioning

confidence: 99%

Effective Dosing Regimen of 1-Aminobenzotriazole for Inhibition of Antipyrine Clearance in Rats, Dogs, and Monkeys

Balani¹,

Zhu²,

Yang³

et al. 2002

Drug Metab Dispos

104

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:1-Aminobenzotriazole (ABT) has been extensively used as a nonspecific inhibitor of cytochromes P450 (P450s) in animals for mechanistic studies, and antipyrine (AP) has been used as a probe for hepatic oxidative metabolic capacity determination in vivo. The method of use of ABT has been variable from lab to lab due largely to unknown pharmacokinetics of ABT itself and incomplete information on various P450s inhibited. The oral pharmacokinetic profiles of ABT were generated in rats, dogs, and monkeys in the dose range of 5 to 200 mg/kg. The results showed that after single oral doses of 50 mg/kg in rats, and 20 mg/kg in dogs and monkeys, the plasma concentrations were high and were sustained for over 24 h. In vitro, inhibition of various expressed P450s upon 30-min preincubation with ABT (0-500 M) showed that CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A4 were inhibited in a dose-dependent manner. The intravenous pharmacokinetics of AP also was affected in a dose-dependent manner in all species, treated 2 h earlier with ABT. Thus, the plasma clearance of AP was inhibited by 88% in rats pretreated with 50 mg/kg ABT and 96% in dogs and 83% in monkeys pretreated with 20 mg/kg ABT. Based on these data in rats, dogs, and monkeys, and the established safety profile of ABT in rats dosed up to 100 mg/kg, a pretreatment at 2 h with a single oral dose of ABT at 100 mg/kg in rats (providing 93% inhibition) and 20 mg/kg in dogs and monkeys effectively inhibited the clearance of the probe compound. ABT1 has been extensively used as a nonspecific inhibitor of cytochromes P450 in animals for mechanistic studies (Mico et al., 1988;Huijzer et al., 1989;Mugford and Tarloff, 1995;Su et al., 1998;Constan et al., 1999;Marczylo and Ioannides, 1999). The method of use of ABT has been quite variable from lab to lab, for example, single versus multiple dosing of animals prior to the test compound, p.o. versus i.v. route of administration, different pretreatment times, and different dose levels. Moreover, the pharmacokinetics of ABT in different species have not been reported. Also there is incomplete information in the literature on the inhibition of P450s by ABT (Knickle and Bend, 1992;Su et al., 1998;Di Re et al., 1999). To provide a guideline for the pretreatment regimen of ABT, 1) single dose oral pharmacokinetic studies were conducted in rats, dogs, and monkeys at several dose levels; 2) in vitro inhibition of various recombinant P450s by ABT was determined; and 3) the effect of selected doses of ABT on the intravenous pharmacokinetics of antipyrine, a probe for measuring efficiency of hepatic oxidative metabolism, was determined. The results from these studies are described in this report. Materials and MethodsABT and antipyrine (AP) were obtained from Sigma-Aldrich (St. Louis, MO). Single oral dose pharmacokinetics of ABT, in 0.5% aqueous methylcellulose, were studied in fasted male Sprague-Dawley rats at 10, 50, and 200 mg/kg (n Ն 3) and in Beagle dogs and Cynomolus m...

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“…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).…”

mentioning

confidence: 99%

Effective Dosing Regimen of 1-Aminobenzotriazole for Inhibition of Antipyrine Clearance in Guinea Pigs and Mice Using Serial Sampling

Balani¹,

Li²,

Nguyen³

et al. 2004

Drug Metab Dispos

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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...

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Distribution of 1-aminobenzotriazole in male rats after administration of an oral dose

Cited by 18 publications

References 6 publications

1-Aminobenzotriazole Modulates Oral Drug Pharmacokinetics through Cytochrome P450 Inhibition and Delay of Gastric Emptying in Rats

1-Aminobenzotriazole Modulates Oral Drug Pharmacokinetics through Cytochrome P450 Inhibition and Delay of Gastric Emptying in Rats

Effective Dosing Regimen of 1-Aminobenzotriazole for Inhibition of Antipyrine Clearance in Rats, Dogs, and Monkeys

Effective Dosing Regimen of 1-Aminobenzotriazole for Inhibition of Antipyrine Clearance in Guinea Pigs and Mice Using Serial Sampling

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