Calcium Antagonists

Rosenthal, Talma; Ezra, David

doi:10.2165/00002018-199513030-00003

Cited by 27 publications

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References 184 publications

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“…However, it is known that calcium channel antagonists sometimes give rise to clinical drugdrug interactions. [1][2][3][4] As one possible explanation for such drug-drug interactions, the inhibition of cytochrome P450 (P450) enzymes, especially CYP3A subfamily enzymes, by calcium channel antagonists has been proposed. 5,6) On the other hand, several calcium channel antagonists have also been reported to induce CYP2B and CYP3A subfamily enzymes in the rat liver [7][8][9] and human primary cultured hepatocytes.…”

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confidence: 99%

Gene Activations of CYP2B1 and CYP3A1 by Dihydropyridine Calcium Channel Antagonists in the Rat Liver: the Structure-Activity Relationship

Konno

Degawa

2004

Biological & Pharmaceutical Bulletin

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Calcium channel antagonists are widely used for the treatment of hypertension. However, it is known that calcium channel antagonists sometimes give rise to clinical drugdrug interactions.1-4) As one possible explanation for such drug-drug interactions, the inhibition of cytochrome P450 (P450) enzymes, especially CYP3A subfamily enzymes, by calcium channel antagonists has been proposed. 5,6) On the other hand, several calcium channel antagonists have also been reported to induce CYP2B and CYP3A subfamily enzymes in the rat liver [7][8][9] and human primary cultured hepatocytes.10) Therefore further studies on not only the inhibition but also the induction of P450 enzymes by calcium channel antagonists are necessary to understand drug-drug interactions.Calcium channel antagonists, including nicardipine (Nic), nifedipine (Nif), verapamil, and diltiazem, are able to induce both CYP2B and CYP3A subfamily enzymes with different selectivity.7-9) Nic and Nif are representative inducers of CYP3A1 and CYP2B1, respectively, among the calcium channel antagonists in the rat liver. 8,9) Although the difference in selectivity between Nic and Nif is assumed to result from the difference in their chemical structure, no study of the structure-activity relationship in the induction of P450 enzymes has been performed.In the present study using dihydropyridine calcium channel antagonists such as Nif, nitrendipine (Nit), nisoldipine (Nis), nimodipine (Nim), and Nic, we examined structureactivity relationships in the activation of CYP2B1 and CYP3A1 in the rat liver and suggest that the length of the side chain at the 3-position of the dihydropyridine ring and the position of the nitro group in the nitrophenyl substituent are important factors for determining the capacity of a dihydropyridine calcium channel antagonist to activate CYP2B1 and CYP3A1. MATERIALS AND METHODSChemicals Nic, Nif, Nim, Nit and Nis were purchased from Wako Pure Chemicals (Osaka, Japan), and their chemical structures are shown in Fig. 1. These chemicals were of the highest grade available.Animals and Treatment Male F344 rats (6 weeks of age) were purchased from Japan SLC Animal (Hamamatsu, Japan), kept in plastic cages in an air-conditioned room, given an MF diet (Oriental Yeast, Tokyo, Japan) and water ad libitum, and used at 7 weeks of age. Rats were treated with one of calcium channel antagonists (200 mmol/kg, p.o.) dissolved in corn oil. 8) Control rats were treated with vehicle alone.RT-PCR Analysis Total hepatic RNA was prepared by the method as described previously 8) and used for the determination of expression levels of CYP2B1 and CYP3A1. In addition, the gene expression level of glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) was measured as an internal control.Complementary DNA (cDNA) was prepared from total We investigated the gene activations of CYP2B1 and CYP3A1 by 1,4-dihydropyridine calcium channel antagonists, including nifedipine (Nif), nisoldipine (Nis), nitrendipine (Nit), nimodipine (Nim), and nicardipine (Nic), in the rat liver and their s...

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Gene Activations of CYP2B1 and CYP3A1 by Dihydropyridine Calcium Channel Antagonists in the Rat Liver: the Structure-Activity Relationship

Konno

Degawa

2004

Biological & Pharmaceutical Bulletin

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“…As a result, the availability of captopril was affected by concurrent administration of H 2 -receptor antagonists [8]. It has been reported that cimetidine reduces metabolism and increases steady state plasma concentrations of several concomitantly administered drugs [9]. Few, but contradictory, data are available on the effects of H 2 -blockers on ACE inhibitor pharmacokinetics [10].…”

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An RP-HPLC method for simultaneous analysis of, and interaction studies on, enalapril maleate and H₂-receptor antagonists

Sultana¹,

Arayne²,

Sattar³

et al. 2009

Acta Chromatographica

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A simple, sensitive, and rapid RP-HPLC method for analysis of enalapril in the presence of H 2 -receptor antagonists has been developed and validated. Enalapril maleate was separated from H 2 -receptor antagonists by use of a 250 mm × 4.6 mm, 5-μm particle, C 18 column with 86:14 (v/v) methanol-water, pH adjusted to 3.5, as mobile phase, at a flow rate of 1.5 mL min −1 . UV detection was performed at 227 nm. The retention times of enalapril maleate, ranitidine, cimetidine, and famotidine were 3, 5, 7, and 7.5 min, respectively. The detection limit for enalapril was 10 ng mL −1 and the calibration plot was linear in the range 2.5-50 μg mL −1 . In-vitro interaction of enalapril with the commonly administered H 2 -receptor antagonists cimetidine, ranitidine, and famotidine in simulated gastric juice at different pH and 37°C was also studied by use of this method. These studies clearly indicated that most of these H 2 -receptor antagonists bind to enalapril causing drastic changes in the availability of the drug. The HPLC method is accurate, selective, sensitive, and reproducible.

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Implications of Cytochrome P450 Interactions When Prescribing Medication for Hypertension

Flockhart¹,

Tanus‐Santos²

2002

Arch Intern Med

129

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Many of the estimated 50 million Americans with high blood pressure receive medications for hypertension and for other conditions, placing them at risk for adverse drug interactions. The risk for hypertension and for adverse drug reactions is highest in the elderly, who have the greatest need for pharmacologic therapy. The most important class of drug interactions involves the cytochrome P450 microsomal enzyme system, which handles a variety of xenobiotic substances. A potential for interactions with these enzymes exists with calcium channel blockers, beta-adrenergic blocking agents, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers but not with diuretic antihypertensives, which are renally eliminated and more vulnerable to drug interactions that occur in the kidney. This article reviews the cytochrome P450 enzyme system, identifies drugs and foods that have been implicated in metabolic interactions with antihypertensive agents, and suggests measures for reducing the risk of adverse events when drugs are coadministered.

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Calcium Antagonists

Cited by 27 publications

References 184 publications

Gene Activations of CYP2B1 and CYP3A1 by Dihydropyridine Calcium Channel Antagonists in the Rat Liver: the Structure-Activity Relationship

Gene Activations of CYP2B1 and CYP3A1 by Dihydropyridine Calcium Channel Antagonists in the Rat Liver: the Structure-Activity Relationship

An RP-HPLC method for simultaneous analysis of, and interaction studies on, enalapril maleate and H₂-receptor antagonists

Implications of Cytochrome P450 Interactions When Prescribing Medication for Hypertension

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Calcium Antagonists

Cited by 27 publications

References 184 publications

Gene Activations of CYP2B1 and CYP3A1 by Dihydropyridine Calcium Channel Antagonists in the Rat Liver: the Structure-Activity Relationship

Gene Activations of CYP2B1 and CYP3A1 by Dihydropyridine Calcium Channel Antagonists in the Rat Liver: the Structure-Activity Relationship

An RP-HPLC method for simultaneous analysis of, and interaction studies on, enalapril maleate and H2-receptor antagonists

Implications of Cytochrome P450 Interactions When Prescribing Medication for Hypertension

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An RP-HPLC method for simultaneous analysis of, and interaction studies on, enalapril maleate and H₂-receptor antagonists