Alterations in the cardiopulmonary effects and pharmacokinetics of a bisphosphonate drug by a cytochrome P-450 inhibitor in conscious rats

Leong, B. K. J.; Sabaitis, C. P.; Rop, D. A.; Jeffrey, Philip D.; Parker, Ted; Burton, Neil; Petry, Thomas; Jolly, Robert A.; Cooper, Maria M.

doi:10.1002/(sici)1099-1263(199709)17:5<279::aid-jat438>3.0.co;2-b

J. Appl. Toxicol.

1997

DOI: 10.1002/(sici)1099-1263(199709)17:5<279::aid-jat438>3.0.co;2-b

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Alterations in the cardiopulmonary effects and pharmacokinetics of a bisphosphonate drug by a cytochrome P-450 inhibitor in conscious rats

B. K. J. Leong¹,

C. P. Sabaitis²,

D. A. Rop³

et al.

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Cited by 5 publications

(1 citation statement)

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“…In mice, intraperitoneal administration of ABT increases brain levels of flurazepam, offering protection against pentylenetetrazole-induced convulsions (Capello et al, 1990). Coadministration of ABT with the bisphosphonate 3-(1,6-dihydro-1-methyl-6-oxo-4-phenyl-2-pyrimidinyl)-propylidene (U-91502) increases drug exposure between 3-and 4-fold; increased exposure was associated with a worsening of cardiovascular side effects, implicating the parent drug rather than metabolites as the toxic compound (Leong et al, 1997).…”

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confidence: 99%

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

Stringer

Weber

Tigani

et al. 2014

Drug Metabolism and Disposition

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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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mentioning

confidence: 99%

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

Stringer

Weber

Tigani

et al. 2014

Drug Metabolism and Disposition

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Utility of food pellets containing 1-aminobenzotriazole for longer term in vivo inhibition of cytochrome P450 in mice

et al. 2018

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1. The utility of 1-aminobenzotriazole (ABT), incorporated in food, has been investigated as an approach for longer term inhibition of cytochrome P450 (P450) enzymes in mice. 2. In rats, ABT inhibits gastric emptying, to investigate this potential limitation in mice we examined the effect of ABT administration on the oral absorption of NVS-CRF38. Two hour prior oral treatment with 100 mg/kg ABT inhibited the oral absorption of NVS-CRF38, T was 4 hours for ABT-treated mice compared to 0.5 hours in the control group. 3. A marked inhibition of hepatic P450 activity was observed in mice fed with ABT containing food pellets for 1 month. P450 activity, as measured by the oral clearance of antipyrine, was inhibited on day 3 (88% of control), week 2 (83% of control) and week 4 (80% of control). 4. T values for antipyrine were comparable between ABT-treated mice and the control group, alleviating concerns about impaired gastric function. 5. Inclusion of ABT in food provides a minimally invasive and convenient approach to achieve longer term inhibition of P450 activity in mice. This model has the potential to enable pharmacological proof-of-concept studies for research compounds which are extensively metabolised by P450 enzymes.

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A commentary on the use of pharmacoenhancers in the pharmaceutical industry and the implication for DMPK drug discovery strategies

Martins¹,

Fazal²,

Oganesian³

et al. 2022

Xenobiotica

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Alterations in the cardiopulmonary effects and pharmacokinetics of a bisphosphonate drug by a cytochrome P-450 inhibitor in conscious rats

Cited by 5 publications

References 3 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

Utility of food pellets containing 1-aminobenzotriazole for longer term in vivo inhibition of cytochrome P450 in mice

A commentary on the use of pharmacoenhancers in the pharmaceutical industry and the implication for DMPK drug discovery strategies

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