SC-435, an ileal apical sodium co-dependent bile acid transporter (ASBT) inhibitor lowers plasma cholesterol and reduces atherosclerosis in guinea pigs.
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.
West
Kristy L
KL
Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA. kristy.west@uconn.edu
Zern
Tosca L
TL
Butteiger
Dustie N
DN
Keller
Bradley T
BT
Fernandez
Maria Luz
ML
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000473:pathology; D001647:Bile Acids and Salts / Q000032:analysis / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D008076:Cholesterol, HDL / Q000097:blood* / Q000187:drug effects; D008078:Cholesterol, LDL / Q000097:blood* / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D006168:Guinea Pigs; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D010316:Particle Size; D011336:Probability; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity; D014326:Tropanes / Q000494:pharmacology*
C466800:1-(4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl)phenoxy)butyl)-4-aza-1-azoniabicyclo(2.2.2)octane; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D003497:Cyclic N-Oxides; D008562:Membrane Glycoproteins; D014326:Tropanes; C037643:bile acid binding proteins