Extrahepatic Metabolism of Carbamate and Organophosphate Thioether Compounds by the Flavin-Containing Monooxygenase and Cytochrome P450 Systems

Furnes, Bjarte; Schlenk, Daniel

doi:10.1124/dmd.104.000984

Cited by 48 publications

(22 citation statements)

References 19 publications

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“…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.…”

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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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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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“…Introduction 1-Aminobenzotriazole (ABT) is a well-established time-dependent inhibitor of cytochrome P450 (P450) enzymes, often used in conjunction with in vitro drug metabolism systems such as microsomes and hepatocytes to determine the relative contribution of P450 enzymes to the metabolism of a drug (Dalmadi et al, 2003;Furnes and Schlenk, 2005;Schulz-Utermoehl et al, 2010). ABT is generally considered as a nonspecific inhibitor of P450; the mechanism of P450 inactivation is likely to be attributed to oxidation of ABT's 1-amino group and decomposition of the molecule yielding reactive benzyne, which forms an NN-bridged adduct on the P450 porphyrin ring (Ortiz de Montellano et al, 1984).…”

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confidence: 99%

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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“…Its structure and function and the implications of its polymorphisms have been widely studied [8,12,13]. This enzyme has a wide substrate specificity, including the dietary-derived tertiary amines trimethylamine, tyramine and nicotine; commonly used drugs including cimetidine, ranitidine, clozapine, methimazole, itopride, ketoconazole, tamoxifen and sulindac sulfide; and agrichemicals, such as organophosphates and carbamates [14][15][16][17][18][19][20][21][22].…”

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Genetic Polymorphisms of Human Flavin-Containing Monooxygenase 3: Implications for Drug Metabolism and Clinical Perspectives

Hisamuddin

Yang

2007

Pharmacogenomics

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Flavin-containing monooxygenase 3 (FMO3) is a hepatic microsomal enzyme that oxidizes a host of drugs, xenobiotics and other chemicals. Numerous variants in the gene encoding FMO3 have been identified, some of which result in altered enzymatic activity and, consequently, altered substrate metabolism. Studies also implicate individual and ethnic differences in the frequency of FMO3 polymorphisms. In addition, new variants continue to be identified with potentially important clinical implications. For example, the role of FMO3 variants in the pathophysiology of gastrointestinal diseases is an evolving area of research. Two commonly occurring polymorphisms of FMO3, E158K and E308G, have been associated with a reduction in polyp burden in patients with familial adenomatous polyposis who were treated with sulindac sulfide, an FMO3 substrate. These findings suggest a potential role for prospective genotyping of common FMO3 polymorphisms in the treatment of disease states that involve the use of drugs metabolized by FMO3. This review summarizes the current state of research on the genetic polymorphisms of FMO3, with a focus on their clinical implications in gastrointestinal diseases. Keywords chemoprevention; familial adenomatous polyposis; flavin-containing monooxygenase 3; gastrointestinal diseases; SNP; sulindac sulfide; trimethylaminuria Humans metabolize a vast array of endogenous and exogenous compounds, including drugs and xenobiotics. It has been observed that different individuals, genders and ethnicities respond differently to the same compounds. This has been attributed to multiple factors, one of which is SNPs. With the completion of the human genome sequence and the discovery of existing SNPs in the genome, interest has focused on the role of genetic polymorphisms of enzymeencoding genes involved in the metabolism of both endogenous and exogenous substances.The flavin-containing monooxygenases (FMOs) belong to a family of flavoprotein enzymes that catalyze the oxidation of a broad array of nucleophilic heteroatom-containing drugs, pesticides and chemicals [1][2][3][4]. There are six human isoforms of flavin-containing monooxygenases, of which five are functional. An additional gene cluster containing five pseudogenes has also been identified in both the human and mouse genome [5][6][7][8][9][10].

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Extrahepatic Metabolism of Carbamate and Organophosphate Thioether Compounds by the Flavin-Containing Monooxygenase and Cytochrome P450 Systems

Cited by 48 publications

References 19 publications

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

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

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

Genetic Polymorphisms of Human Flavin-Containing Monooxygenase 3: Implications for Drug Metabolism and Clinical Perspectives

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