ArticleBritish journal of clinical pharmacology2001
Inhibitory effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes.
Article in British journal of clinical pharmacology, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 81 citations in OpenAlex.
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- Clinical outcomes and management of mechanism-based inhibition of cytochrome P450 3A4.Therapeutics and clinical risk management · 2005Article
- Effect of benzodiazepines on the metabolism of buprenorphine in human liver microsomes.European journal of clinical pharmacology · 2005Article
- Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs.Clinical pharmacokinetics · 2005Review
- Prevalence of potentially severe drug-drug interactions in ambulatory patients with dyslipidaemia receiving HMG-CoA reductase inhibitor therapy.Drug safety · 2005Article
- Serum Rifampicin Levels in Patients with Tuberculosis : Effect of P-Glycoprotein and CYP3A4 Blockers on its Absorption.Clinical drug investigation · 2003Article
- Cytochrome P450 drug interactions within the HMG-CoA reductase inhibitor class: are they clinically relevant?Drug safety · 2003Review
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsTo determine the effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes and to compare their inhibitory potencies and CYP3A4 inactivation parameters with those reported previously for mibefradil.
methodsSimvastatin metabolism was investigated in human liver microsomes in the presence and absence of verapamil or diltiazem (0.1-250 microM). Kinetics of CYP3A4 inactivation by verapamil and diltiazem were determined using testosterone as the substrate.
resultsWhen verapamil was coincubated with simvastatin, IC50 values ranged from 23 to 26 microM for all major metabolites. The IC50 values ranged from 4.8 to 5.6 microM on preincubation of verapamil for 30 min in the presence of an NADPH-generating system. Corresponding IC50 values for diltiazem ranged from 110-127 microM and from 21-27 microM, respectively. Verapamil and diltiazem inhibited testosterone 6beta-hydroxylation in a time- and concentration-dependent manner, key features of mechanism-based inactivation. Values for the inactivation parameters kinact and KI were 0.15 +/- 0.04 min-1 (mean +/- s.d.) and 2.9 +/- 0.6 microM, respectively, for verapamil and 0.07 +/- 0.01 min-1 and 3.3 +/- 1.5 microM, respectively, for diltiazem.
conclusionsThe IC50 values for coincubation of verapamil and diltiazem were 46- and 220-fold higher, respectively, than those reported previously for mibefradil, and 16- and 71-fold higher, respectively, for preincubation. Thus, the results of this study suggest that verapamil and diltiazem are less likely than mibefradil to cause acute drug interactions with simvastatin in vivo. However, verapamil and diltiazem are moderate mechanism-based inhibitors of CYP3A4 and therefore may still cause significant inhibition of simvastatin metabolism in vivo during chronic therapy.
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