The synergistic hypocholesterolemic activity of the potent cholesterol absorption inhibitor, ezetimibe, in combination with 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors in dogs.
Ezetimibe (SCH 58235) and SCH 48461 are potent cholesterol absorption inhibitors, which cause significant decreases in plasma cholesterol levels in cholesterol-fed animals and in humans with hypercholesterolemia. These compounds selectively block intestinal uptake and absorption of cholesterol. These cholesterol absorption inhibitors cause modest, inconsistent reductions in plasma cholesterol levels in animals fed cholesterol-free chow diets. Although, these compounds block cholesterol absorption and increase neutral sterol excretion, chow-fed animals compensate for the loss of biliary cholesterol by increasing hepatic cholesterol synthesis. Therefore, we determined the effect of SCH 48461 and ezetimibe in combination with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors in chow-fed dogs. A synergistic reduction in plasma cholesterol was observed in chow-fed dogs given SCH 48461 (0.1 mg/kg/d) and the HMG CoA reductase inhibitor, lovastatin (5 mg/kg/d). Neither SCH 48461 nor lovastatin alone affected plasma cholesterol levels. Their combination for 14 days caused a 36% reduction in plasma cholesterol levels from 129 mg/dL to 83 mg/dL (P <.05). Ezetimibe (0.007 mg/kg/d) also caused synergistic reductions in plasma cholesterol levels in chow-fed dogs when combined with HMG CoA reductase inhibitors for 2 weeks (5 mg/kg lovastatin -50%; 2.5 mg/kg pravastatin -41%; 5 mg/kg fluvastatin -60%, and -30% with low doses of simvastatin and atorvastatin 1 mg/kg). The combination of this class of cholesterol absorption inhibitors with an HMG CoA reductase inhibitor should be very effective clinically at reducing plasma cholesterol levels, even with reduced dietary intake of cholesterol.
Davis
H R
HR
Department of CNS and Cardiovascular Research, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Pula
K K
KK
Alton
K B
KB
Burrier
R E
RE
Watkins
R W
RW
D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001384:Azetidines / Q000008:administration & dosage / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood*; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004285:Dogs; D004338:Drug Combinations; D004357:Drug Synergism; D000069438:Ezetimibe; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000139:chemically induced / Q000517:prevention & control*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008148:Lovastatin / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D017035:Pravastatin / Q000008:administration & dosage / Q000494:pharmacology; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors
D000924:Anticholesteremic Agents; D001384:Azetidines; D002791:Cholesterol, Dietary; D004338:Drug Combinations; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D008148:Lovastatin; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D000069438:Ezetimibe; D017035:Pravastatin