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Effects of simvastatin on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, after oral and intravenous administration in rats: possible role of P-glycoprotein and CYP3A4 inhibition by simvastatin

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Abstract

The purpose of this study was to investigate the possible effects of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats. HMG-CoA reductase inhibitors and diltiazem are sometimes prescribed as a combination therapy for the prevention or treatment of cardiovascular diseases. The effect of simvastatin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was evaluated. Simvastatin inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibition concentration (IC50) of 3.0 μM. In addition, simvastatin significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. The pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined after oral and intravenous administration of diltiazem to rats in the presence and absence of simvastatin (0.3 and 1.0 mg/kg). The areas under the plasma concentration-time curve (AUC) and the peak concentration (Cmax) of diltiazem were significantly (p < 0.05, 1.0 mg/kg) increased by 45.2% and 35.2%, respectively, in the presence of simvastatin compared to control. Consequently, the absolute bioavailability (AB) values of diltiazem in the presence of simvastatin (1.0 mg/kg) were significantly (p < 0.05) higher (44.8%) than that of the control group. Moreover, the relative bioavailability (RB) of diltiazem was 1.21- to 1.45-fold greater than that in the control group. The metabolite-parent AUC ratio (MR) in the presence of simvastatin (1.0 mg/kg) significantly decreased compared to the control group. This result implied that simvastatin effectively inhibited the metabolism of diltiazem.

The increase in diltiazem oral bioavailability might be attributable to enhanced absorption in the small intestine via the inhibition of P-gp and to reduced first-pass metabolism of diltiazem via the inhibition of the CYP3A subfamily in the small intestine and/or in the liver rather than renal elimination of diltiazem by simvastatin.

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Abbreviations

AB (%):

absolute bioavailability

AUC:

area under the plasma concentration-time curve

Cmax:

peak plasma concentration

Ka:

absorption rate constant for the diltiazem

K12:

distribution rate constant of the drug from the central compartment to the peripheral compartment

K21:

distribution rate constant from the peripheral compartment to the central compartment

MR:

metabolite-parent ratio

RB (%):

relative bioavailability

t1/2:

terminal half-life

Tmax:

time to peak concentration

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Authors and Affiliations

  1. College of Medicine, Chosun University, Gwangju, 501-759, Korea

    Dong-Hyun Choi

  2. Department of Food and Drug, Chosun University, Gwangju, 501-759, Korea

    Jin-Seok Choi

  3. College of Pharmacy, Chosun University, Gwangju, 501-759, Korea

    Cheng Li & Jun-Shik Choi

  4. College of Pharmacy, Yanbian University, Jilin, 133-000, China

    Cheng Li

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  1. Dong-Hyun Choi
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  2. Jin-Seok Choi
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Correspondence to Jun-Shik Choi.

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Choi, DH., Choi, JS., Li, C. et al. Effects of simvastatin on the pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, after oral and intravenous administration in rats: possible role of P-glycoprotein and CYP3A4 inhibition by simvastatin. Pharmacol. Rep 63, 1574–1582 (2011). https://doi.org/10.1016/S1734-1140(11)70724-1

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  • DOI: https://doi.org/10.1016/S1734-1140(11)70724-1

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