Pharmacokinetic and Pharmacodynamic interaction between Simvastatin and Diltiazem in rats with induced hypercholesterolaemia and hypertension




3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are often prescribed along with antihypertensive agents, including calcium antagonists. Simvastatin is an HMG-CoA reductase inhibitor and Diltiazem which calcium antagonist it is metabolized by the cytochrome P450 (CYP) 3A4. The purpose of this study is to investigate drug interactions between simvastatin and diltiazem. In the present investigation, we studied the pharmacokinetics and dynamics of Simvastatin (SIMVA) alone and in combination with Diltiazem (DILT) in hyperlipidemic and hypertensive rats. The standard cholesterol diet was used to induce hyperlipidemia and 10% fructose solution was used to induce hypertension in Wistar rats. The selected drugs were given for 2 weeks by oral route, simvastatin (2 mg/day), followed by 2 weeks of oral diltiazem (15 mg/day) co-administered with simvastatin (2 mg/day). Combined treatment with simvastatin and diltiazem increased the peak concentration (Cmax) of HMG-CoA reductase inhibitors from 15.64 ± 0.29 µg/mL to 19.45 ± 0.07  (P < 0.01) and the area under the concentration-time curve (AUC) from 60.19 ± 2.24  µg h/mL to 78.4±  0.80 µg h/mL (P < 0.01) without affecting the cholesterol-lowering effect of simvastatin. In hyperlipidemic rats, SIMVA caused a marked reduction in the lipid profiles but combination with DILT produced a significant change. In pharmacokinetics, witnessed insignificant change in the combination of SIMVA and DILT when compared with SIMVA alone. From the results synergistic activity of SIMVA with DILT was witnessed.



Magro L, Conforti A, Del Zotti F, Leone R, Iorio ML, Meneghelli I, et al. Identification of severe potential drug-drug interactions using an Italian general-practitioner database. Eur J Clin Pharmacol. 2008;64(3):303-9.

Wiwanitkit V, Wangsaturaka D, Tangphao O. LDL-cholesterol lowering effect of a generic product of simvastatin compared to simvastatin (Zocor) in Thai hypercholesterolemic subjects -- a randomized crossover study, the first report from Thailand. BMC clinical pharmacology. 2002;2:1-6.

Basile J. The Role of Existing and Newer Calcium Channel Blockers in the Treatment of Hypertension. J Clin Hypertens. 2004;6(11):621-9.

Grossman E, Messerli FH. Calcium antagonists. Prog Cardiovasc Dis. 2004;47(1):34-57.

Prueksaritanont T, Ma B, Yu N. The human hepatic metabolism of simvastatin hydroxy acid is mediated primarily by CYP3A, and not CYP2D6. Brit J Clin Pharmacol. 2003;56(1):120-4.

Katoh M, Nakajima M, Shimada N, Yamazaki H, Yokoi T. Inhibition of human cytochrome P450 enzymes by 1,4-dihydropyridine calcium antagonists: prediction of in vivo drug–drug interactions. Eur J Clin Pharmacol. 2000;55(11-12):843-52.

Sutton D, Butler AM, Nadin L, Murray M. Role of CYP3A4 in Human Hepatic Diltiazem N-Demethylation: Inhibition of CYP3A4 Activity by Oxidized Diltiazem Metabolites. J Pharmacol Exp Therap. 1997 July 1, 1997;282(1):294-300.

Chaffman M, Brogden RN. Diltiazem. Drugs. 1985;29(5):387-454.

Hansson L, Hedner T, Lund-Johansen P, Kjeldsen SE, Lindholm LH, Syvertsen JO, et al. Randomised trial of effects of calcium antagonists compared with diuretics and β-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet. 2000;356(9227):359-65.

Yeung Pollen KF, Feng Joe DZ, Buckley Susan J. Pharmacokinetics and Hypotensive Effect of Diltiazem in Rabbits after a Single Intravenous Administration: Effect of Phenobarbital. Drug Metab Drug Interact. 1998;14(3):179-92.

Höglund P, Nilsson L-G. Pharmacokinetics of Diltiazem and Its Metabolites After Repeated Multiple-Dose Treatments in Healthy Volunteers. Ther Drug Monit. 1989;11(5):543-50.

Kumar KP, Reddy ARN, Anbu J, Reddy YN. Simultaneous determination of atorvastatin and lercanidipine in rat plasma by HPLC and pharmacokinetic studies. Asian J Pharmacokin Pharmacodyn. 2008;8:299-304.

Vijaya Kumar M, Muley P. RP HPLC Determination of Lercanidipine in Bulk Drug and Solid Dosage Forms. Indian Drugs. 2004;41(1):24-7.

Allain CC, Poon LS, Chan CSG, Richmond W, Fu PC. Enzymatic Determination of Total Serum Cholesterol. Clin Chem. 1974;20(4):470-5.

Werner M, Gabrielson DG, Eastman J. Ultramicro determination of serum triglycerides by bioluminescent assay. Clin Chem. 1981;27(2):268-71.

Friedewald WT, Levy RI, Fredrickson DS. Estimation of the Concentration of Low-Density Lipoprotein Cholesterol in Plasma, Without Use of the Preparative Ultracentrifuge. Clin Chem. 1972;18(6):499-502.

Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.