Atherosclerosis 171 (2003) 201–210 SC-435, an ileal apical sodium co-dependent bile acid transporter (ASBT) inhibitor lowers plasma cholesterol and reduces atherosclerosis in guinea pigs Kristy L. West a,∗ , Tosca L. Zern a , Dustie N. Butteiger b , Bradley T. Keller b , Maria Luz Fernandez a a Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA b Pharmacia Corporation, T2K/800 N. Lindbergh Boulevard, St. Louis, MO 63167, USA Received 26 February 2003; received in revised form 30 June 2003; accepted 15 August 2003 Abstract Male Hartley guinea pigs were randomly allocated to one of four treatments, 10 guinea pigs per group, for 12 weeks. The control diet contained no ASBT inhibitor (ASBTi) or simvastatin. Low ASBTi (LowASBTi) and high ASBTi (HighASBTi) were monotherapies containing 0.03 g/100 g and 0.1 g/100 g of the ASBTi SC-435. Combination therapy (COMBO) was a combination therapy consisting of 0.03 g/100 g ASBTi and 0.05 g/100 g simvastatin. Based on food consumption, guinea pigs received 17.2 and 47.8 mg/kg per day ASBTi in the ASBTi groups or 13.7 mg/kg per day ASBTi and 21.4 mg/kg per day simvastatin in the COMBO group. The amount of cholesterol in each diet was 0.25 g/100 g. LDL cholesterol was 40 and 70% lower with the HighASBTi and COMBO treatments compared to controls. Plasma triglycerides (TG) were 70% lower with COMBO therapy while HDL cholesterol was 43–47% higher with all treatments. Hepatic free cholesterol was reduced 60–80% with all treatments. Cholesterol content in the aortic arch was reduced by 25 and 42% in the HighASBTi and COMBO groups. Fecal bile acids were increased by 2.5- and 4-fold with HighASBTi and COMBO treatments. These data suggest that the interruption in the enterohepatic circulation of bile acids by ASBTi and statin co-administration therapy cause a significant reduction in plasma cholesterol concentrations and attenuate the progression of atherosclerosis in guinea pigs. © 2003 Published by Elsevier Ireland Ltd. Keywords: ASBT: apical sodium co-dependent bile acid transporter; LDL cholesterol; Atherosclerosis; Simvastatin; Bile acids; Lipoproteins; Guinea pigs 1. Introduction Elevated concentrations of low-density lipoproteins (LDL) have been shown to increase the risk for coronary heart disease (CHD) and atherosclerosis [1]. The US Na- tional Cholesterol Education Program (NCEP) Adult Treat- ment Panel (APT) III emphasizes that patients with CHD or risk of CHD >20% over 10 years and LDL cholesterol (LDL-C) levels >130 mg/dl should receive drug therapy with a goal of reducing LDL-C to <100 mg/dl [1]. Primary prevention of CHD and atherosclerosis includes reduced Abbreviations: ASBT, apical sodium co-dependent bile acid trans- porter; ASBT, cholesterol 7-hydroxylase; CYP7A, cholesteryl ester; CE, combination therapy; COMBO, free cholesterol; FC, triglycerides: TG. ∗ Corresponding author. Tel.: +1-860-486-5547; fax: +1-860-486-3674. E-mail address: kristy.west@uconn.edu (K.L. West). intakes of saturated fat and cholesterol, increased activity and weight control [1]. Nonetheless, dietary measures are frequently combined with drug treatments for high-risk in- dividuals. To date, statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, and bile acid sequestrants are commonly used in clinical practice to lower LDL-C to recommended levels. However, elevated LDL-C is not the only cause of atherosclerosis. In addition, large doses of bile acid sequestrants are required for effec- tive cholesterol reductions and many patients complain of gastrointestinal side effects, which can result in poor patient compliance [2]. Consequently, researchers continue to look for a more effective treatment for CHD and atherosclerosis. The enterohepatic circulation of bile acids requires effi- cient bile acid absorption by the ileum. Bile acids are syn- thesized from cholesterol in the liver and secreted with bile into the small intestine, where they facilitate the absorption of fat, fat-soluble vitamins, and cholesterol [3]. Bile acids 0021-9150/$ – see front matter © 2003 Published by Elsevier Ireland Ltd. doi:10.1016/j.atherosclerosis.2003.08.019