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

Stringer, Rowan; Weber, Eckhard; Tigani, Bruno; Lavan, Paul; Medhurst, Stephen J.; Sohal, Bindi

doi:10.1124/dmd.113.056408

Cited by 21 publications

(17 citation statements)

References 21 publications

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“…These results are consistent with the study of Stringer et al (2014), who demonstrates with a fluorescent marker that ABT inhibits the gastric emptying when dosed p.o. or intraperitoneally 2 hours before the test meal.…”

Section: Effect Of Abt On Pharmacokinetics Of Metoprolol In Rats 1963supporting

confidence: 82%

“…In addition, most studies report changes in the pharmacokinetic profiles of the probe substrates but few have examined the corresponding changes in the pharmacokinetic profiles of the circulating metabolites. This may lead to misinterpretation of the impact of ABT on in vivo metabolism in light of the recent report that ABT may also affect intestinal transit time (Stringer et al, 2014). Finally, none of these studies have undertaken a systematic approach to measure the impact of ABT pretreatment on the role of gut and liver metabolism.…”

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confidence: 96%

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In Vitro and In Vivo Mechanistic Studies toward Understanding the Role of 1-Aminobenzotriazole in Rat Drug-Drug Interactions

et al. 2015

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1-Aminobenzotriazole (ABT) is regularly used in vivo as a nonspecific and irreversible cytochrome P450 inhibitor to elucidate the role of metabolism on the pharmacokinetic profile of xenobiotics. However, few reports have considered the recent findings that ABT can alter drug absorption or have investigated the possible differential inhibition of ABT on intestinal and hepatic metabolism. To address these uncertainties, pharmacokinetic studies under well controlled and defined ABT pretreatment conditions (50 mg/kg, 1 hour ABT i.v. and 16 hours ABT p.o.) were conducted prior to the oral administration of metoprolol, a permeable P450 probe that undergoes extensive intestinal and hepatic metabolism. The pharmacokinetic profile of metoprolol was affected differently by the two ABT pretreatments. An increase in area under the curve of 16-fold with ABT p.o. and 6.5-fold with ABT i.v. was observed compared with control. Based on in vitro studies, this difference could not be attributed to a differential inhibition of intestinal and hepatic metabolism. In the ABT i.v. pretreatment group, the increase in area under the curve was also associated with a prolonged time at maximal concentration (24-fold versus control), suggesting a delay in absorption. This was further confirmed by the administration of a charcoal meal, which resulted in a 7-fold increase in stomach weights in the 1-hour ABT pretreated groups compared with the untreated or 16-hour ABT pretreated rats. Based on these results, we recommend pretreating rats with ABT p.o. 16 hours before the administration of a test compound to preserve the inhibitory effect on intestinal and hepatic metabolism and avoid the confounding effect on drug absorption.

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Section: Effect Of Abt On Pharmacokinetics Of Metoprolol In Rats 1963supporting

confidence: 82%

mentioning

confidence: 96%

In Vitro and In Vivo Mechanistic Studies toward Understanding the Role of 1-Aminobenzotriazole in Rat Drug-Drug Interactions

et al. 2015

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“…2b vs. a). It might also result from an ABT-induced enhancement of overall absorption of D and DA from the gastrointestinal tract since ABT could delay gastric emptying in rodents (Stringer et al, 2014), affording more systemic D and DA for conversion to DOH. These possibilities are presently under investigation.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 Isoforms in the Metabolism of Decursin and Decursinol Angelate from Korean Angelica

Zhang

Tang

et al. 2015

Am. J. Chin. Med.

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We have shown that the in vitro hepatic microsomal metabolism of pyranocoumarin compound decursinol angelate (DA) to decursinol (DOH) exclusively requires cytochrome P450 enzymes (CYP) whereas the conversion of its isomer decursin (D) to DOH can be mediated by CYP and esterase(s). To provide insight into specific isoforms involved, here we show with recombinant human CYP that 2C19 was the most active at metabolizing D and DA in vitro followed by 3A4. With carboxylesterases (CES), D was hydrolyzed by CES2 but not CES1, and DA was resistant to both CES1 and CES2. In human liver microsomal preparation, general CYP inhibitor 1-aminobenzotriazole (ABT) and respective competitive inhibitors for 2C19 and 3A4, (+)-N-3-benzylnirvanol and ketoconazole, substantially retarded the metabolism of DA and, to a lesser extent, of D. In healthy human subjects from a single-dose pharmacokinetic study, 2C19 extensive metabolizer genotype (2C19*17 allele) tended to have less plasma DA AUC0–48h and poor metabolizer genotype (2C19*2 allele) tended to have greater DA AUC0–48h. In mice given a single dose of D/DA, pretreatment with ABT boosted the plasma and prostate levels of D and DA by more than an order of magnitude. Taken together, our findings suggest that CYP isoforms 2C19 and 3A4 may play a crucial role in the first pass liver metabolism of DA and, to a lesser extent, that of D in humans. Pharmacogenetics with respect to CYP genotypes and interactions among CYP inhibitor drugs and D/DA should therefore be considered in designing future translation studies of DA and/or D.

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“…When ABT is applied as an integral part of in vivo pharmacology studies, it is of particular importance to evaluate the effect of ABT on the pharmacological readout in question. On the basis of previous ABT interaction studies in rats (Stringer et al, 2014), caution is recommended when using ABT in vivo with orally administered compounds. Further studies would be of value to evaluate the risk of impaired gastric emptying in mice.…”

Section: Resultsmentioning

confidence: 99%

“…Introduction 1-Aminobenzotriazole (ABT) is a time-dependant inhibitor of cytochrome P450 (P450) enzymes (Ortiz de Montellano et al, 1984) and is often used as a tool compound for in vitro (Furnes and Schlenk, 2005) and in vivo (Stringer et al, 2014;Boily et al, 2015) drug metabolism studies. The utility of ABT for in vivo P450 inhibition has been evaluated in a range of species, including mice, rats, guinea pigs, dogs, and monkeys (Balani et al, 2002(Balani et al, , 2004.…”

mentioning

confidence: 99%

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

Stringer

Ferreira

Rose

et al. 2016

Drug Metabolism and Disposition

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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 longerterm 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. Introduction1-Aminobenzotriazole (ABT) is a time-dependant inhibitor of cytochrome P450 (P450) enzymes (Ortiz de Montellano et al., 1984) and is often used as a tool compound for in vitro (Furnes and Schlenk, 2005) and in vivo (Stringer et al., 2014;Boily et al., 2015) drug metabolism studies. The utility of ABT for in vivo P450 inhibition has been evaluated in a range of species, including mice, rats, guinea pigs, dogs, and monkeys (Balani et al., 2002(Balani et al., , 2004. For each species, efficient inhibition of metabolism was demonstrated with antipyrine, a nonspecific substrate of P450 enzymes (Engel et al., 1996;Sharer and Wrighton, 1996). To avoid the need for repeated ABT administration, we have explored the use of osmotic pumps as a technology to achieve sustained release of ABT and sustained inhibition of P450 enzymes in mice.To assess the effectiveness of the in vivo ABT approach, we compared the degree of P450 inhibition using this method with that in the hepatic reductase null (HRN) mouse. The HRN mouse only has residual hepatic P450 activity as a result of a liver-specific knockout of the P450 reductase enzyme during the postnatal period (Henderson et al., 2003), and extrahepatic P450 is unaffected. Marked differences in drug disposition have been observed in HRN mice compared with wild-type mice (Pickup et al., 2012;Boggs et al., 2014;Grimsley et al., 2014). After a single bolus dose of ABT to mice, the duration of inhibitory activity was relatively short: clearance of antipyrin...

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

Cited by 21 publications

References 21 publications

In Vitro and In Vivo Mechanistic Studies toward Understanding the Role of 1-Aminobenzotriazole in Rat Drug-Drug Interactions

In Vitro and In Vivo Mechanistic Studies toward Understanding the Role of 1-Aminobenzotriazole in Rat Drug-Drug Interactions

Cytochrome P450 Isoforms in the Metabolism of Decursin and Decursinol Angelate from Korean Angelica

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

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