title: Opposite effects of bezafibrate and gemfibrozil in both normal and hypertriglyceridemic rats.
abstract: Chow and sucrose-fed rats were used as animal models to study the dose-responses of bezafibrate and gemfibrozil in normolipidemic and hypertriglyceridemic states, respectively. Although both drugs lowered plasma triglycerides (TG) to about the same extent in chow-fed rats, gemfibrozil lowered liver TG as well as plasma total and LDL-cholesterol (LDL-C), but elevated HDL-cholesterol (HDL-C) and plasma apo E concentrations. Bezafibrate produced opposite effects, namely, decreased HDL-C, apo E and liver TG, and tended to increase LDL-C. TG lowering for both drugs in chow-fed rats was not due to changes in TG secretion (production) in normal rats but was associated with enhanced LPL activity. In hypertriglyceridemic rats both drugs modestly reduced TG secretion rates about 40% at a dose producing maximal TG lowering, but again, gemfibrozil elevated and bezafibrate lowered HDL-C and apo E. Unlike gemfibrozil, bezafibrate induced the appearance of LDL-C in hypertriglyceridemic rats which was not detected in control animals, and also tended to increase rather than decrease plasma apo B levels. Finally, changes in liver TG concentration (mg/g) in hypertriglyceridemic rats were opposite for these drugs, resulting in significant drug-related differences in liver TG content (mg/organ). From these data we postulate that, although similar with regard to TG lowering activity and mechanisms thereof, gemfibrozil and bezafibrate produce fundamentally different effects on LDL, HDL and apolipoprotein metabolism (apo B and apo E) in rats which may relate to potential differential effects on reverse cholesterol transport and atherogenesis.
authors.affiliation: Vascular and Cardiac Diseases, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48103 USA. kraus01@aa.wl.com
authors.forename: B R
authors.initials: BR
authors.lastname: Krause
authors.forename: B C
authors.initials: BC
authors.lastname: Barnett
authors.forename: A D
authors.initials: AD
authors.lastname: Essenburg
authors.forename: K A
authors.initials: KA
authors.lastname: Kieft
authors.forename: B J
authors.initials: BJ
authors.lastname: Auerbach
authors.forename: R
authors.initials: R
authors.lastname: Bousley
authors.forename: R
authors.initials: R
authors.lastname: Stanfield
authors.forename: R S
authors.initials: RS
authors.lastname: Newton
authors.forename: C L
authors.initials: CL
authors.lastname: Bisgaier
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000097:blood; D001057:Apolipoproteins E / Q000097:blood; D001629:Bezafibrate / Q000008:administration & dosage / Q000494:pharmacology*; D001835:Body Weight; D002784:Cholesterol / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood; D004305:Dose-Response Relationship, Drug; D015248:Gemfibrozil / Q000008:administration & dosage / Q000494:pharmacology*; D015228:Hypertriglyceridemia / Q000188:drug therapy* / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007122:Immunoelectrophoresis; D008071:Lipoprotein Lipase / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013053:Spectrophotometry; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001055:Apolipoproteins B; D001057:Apolipoproteins E; D008078:Cholesterol, LDL; D000960:Hypolipidemic Agents; D014280:Triglycerides; D002784:Cholesterol; D008071:Lipoprotein Lipase; D015248:Gemfibrozil; D001629:Bezafibrate