title: Pharmacokinetic and pharmacodynamic interactions between simvastatin and diltiazem in patients with hypercholesterolemia and hypertension.
abstract: Pharmacokinetic and pharmacodynamic interactions between simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and diltiazem, a calcium antagonist, were investigated in 7 male and 4 female patients with hypercholesterolemia and hypertension. The patients were given, for one in a three consecutive 4-week periods, oral simvastatin (5 mg/day), oral simvastatin (5 mg/day) combined with diltiazem (90 mg/day), and then oral diltiazem (90 mg/day), respectively. The area under the plasma concentration versus time curve up to 6 hours post-dose (AUC0-6h) and maximum plasma concentrations (Cmax) of the drugs, serum lipid profiles, blood pressures and liver functions were assessed on the last day of each of the three 4-week periods. After the combined treatment period, Cmax of HMG-CoA reductase inhibitor was elevated from 7.8 +/- 2.6 ng/ml to 15.4 +/- 7.9 ng/ml (P < 0.01) and AUC0-6h from 21.7 +/- 4.9 ng x hr/ml to 43.3 +/- 23.4 ng x hr/ml (P < 0.01), while Cmax of diltiazem was decreased from 74.2 +/- 36.4 ng/ml to 58.6 +/- 18.9 ng/ml (P < 0.05) and its AUC0-6h from 365 +/- 153 ng x hr/ml to 287 +/- 113 ng x hr/ml (P < 0.01). Compared to simvastatin monotherapy, combined treatment further reduced LDL-cholesterol levels by 9%, from 129 +/- 16 mg/dl to 119 +/- 17 mg/dl (P < 0.05). No adverse events were observed throughout the study. These apparent pharmacokinetic interactions, namely the increase of HMG-CoA reductase inhibitor concentration by diltiazem and the decrease of diltiazem concentration by simvastatin, enhance the cholesterol-lowering effects of simvastatin during combined treatment.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan. hwat@hama-med.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kosuge
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Nishio
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamada
authors.forename: Shinya
authors.initials: S
authors.lastname: Uchida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Satoh
authors.forename: Hideharu
authors.initials: H
authors.lastname: Hayashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishizaki
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Ohashi
mesh_terms: D000284:Administration, Oral; D019540:Area Under Curve; D001794:Blood Pressure; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004110:Diltiazem / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000378:metabolism*; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D019821:Simvastatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016896:Treatment Outcome
chemical_list: D002121:Calcium Channel Blockers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D019821:Simvastatin; D004110:Diltiazem