In vivo oxidative cleavage of a pyridinecarboxylic acid ester metabolite of nifedipine

Funaki, Takashi; Pa, Soons; Fp, Guengerich; Dd, Breimer

doi:10.1016/0006-2952(89)90517-0

Cited by 37 publications

(21 citation statements)

References 20 publications

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“…The oxidation seems to be mostly catalyzed by the 3A4 isoform of the cytochrome P450 enzymes (Katoh et al, 2000). It was also demonstrated that CYP3A4 was capable of oxidative cleavage of the ester bond in nifedipine (Funaki et al, 1989). To our knowledge, no study has investigated a potential role of esterases in hydrolytic cleavage of ester bonds at the 3 or 5 position in dihydropyridine calcium antagonists.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Drug Metabolism by Human Carboxylesterase 1: Focus on Angiotensin-Converting Enzyme Inhibitors

Thomsen

Rasmussen

Línnet

2014

Drug Metabolism and Disposition

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Carboxylesterase 1 (CES1) is the major hydrolase in human liver. The enzyme is involved in the metabolism of several important therapeutic agents, drugs of abuse, and endogenous compounds. However, no studies have described the role of human CES1 in the activation of two commonly prescribed angiotensinconverting enzyme inhibitors: enalapril and ramipril. Here, we studied recombinant human CES1-and CES2-mediated hydrolytic activation of the prodrug esters enalapril and ramipril, compared with the activation of the known substrate trandolapril. Enalapril, ramipril, and trandolapril were readily hydrolyzed by CES1, but not by CES2. Ramipril and trandolapril exhibited Michaelis-Menten kinetics, while enalapril demonstrated substrate inhibition kinetics. Intrinsic clearances were 1.061, 0.360, and 0.02 ml/min/mg protein for ramipril, trandolapril, and enalapril, respectively. Additionally, we screened a panel of therapeutic drugs and drugs of abuse to assess their inhibition of the hydrolysis of p-nitrophenyl acetate by recombinant CES1 and human liver microsomes. The screening assay confirmed several known inhibitors of CES1 and identified two previously unreported inhibitors: the dihydropyridine calcium antagonist, isradipine, and the immunosuppressive agent, tacrolimus. CES1 plays a role in the metabolism of several drugs used in the treatment of common conditions, including hypertension, congestive heart failure, and diabetes mellitus; thus, there is a potential for clinically relevant drug-drug interactions. The findings in the present study may contribute to the prediction of such interactions in humans, thus opening up possibilities for safer drug treatments.

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Section: Discussionmentioning

confidence: 99%

In Vitro Drug Metabolism by Human Carboxylesterase 1: Focus on Angiotensin-Converting Enzyme Inhibitors

Thomsen

Rasmussen

Línnet

2014

Drug Metabolism and Disposition

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“…In humans, nifedipine is predominantly metabolized by CYP3A4 to its primary pyridine metabolite, dehydronifedipine (Funaki et al, 1989;Ohno et al, 2007). CYP3A4 is the most abundant CYP enzyme (30-40%) in the adult liver and it metabolizes more than 50% of clinically used drugs, including nifedipine (Shimada et al, 1994).…”

Section: Nifedipinementioning

confidence: 98%

Drug–drug interactions of silymarin on the perspective of pharmacokinetics

Lin

Tsai

2009

Journal of Ethnopharmacology

166

116

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“…In humans, NIF is predominantly metabolized by cytochrome P450 (CYP3A4) to its primary pyridine metabolite, dehydronifedipine (DNIF, II; Fig. 1) [6,7]. The C max values of DNIF vary from 8 to 37 ng/mL after an oral dose of 10 mg NIF [4,5].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, the quantitative measurement of CYP3A4 activity in humans is important to explore the effects of environmental, physiological, pathological and pharmacogenetic factors on the expression of CYP3A4 gene. NIF, together with a few other typical CYP3A4 substrates including erythromycin (N-demethylation), midazolam (1-hydroxylation), testosterone (6␤-hydroxylation), triazolam (1-hydroxylation), cortisol (6␤-hydroxylation) and terfenadine (t-butylhydroxylation), have been commonly used as probe drugs when determining phenotypic CYP3A4 activity in humans [6,7,[11][12][13][14][15][16][17]. The ratio of plasma levels of the resultant oxidized metabolite to those of the parental drug is often used as a reliable indicator of CYP3A4 activity.…”

Section: Introductionmentioning

confidence: 99%

Rapid and simultaneous determination of nifedipine and dehydronifedipine in human plasma by liquid chromatography–tandem mass spectrometry: Application to a clinical herb–drug interaction study

Wang

et al. 2007

Journal of Chromatography B

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In vivo oxidative cleavage of a pyridinecarboxylic acid ester metabolite of nifedipine

Cited by 37 publications

References 20 publications

In Vitro Drug Metabolism by Human Carboxylesterase 1: Focus on Angiotensin-Converting Enzyme Inhibitors

In Vitro Drug Metabolism by Human Carboxylesterase 1: Focus on Angiotensin-Converting Enzyme Inhibitors

Drug–drug interactions of silymarin on the perspective of pharmacokinetics

Rapid and simultaneous determination of nifedipine and dehydronifedipine in human plasma by liquid chromatography–tandem mass spectrometry: Application to a clinical herb–drug interaction study

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