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.
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. http://dx.doi.org/10.1016/S0140-6736(00)02526-5
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. .168
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.