Atorvastatin enhances the plasma clearance of chylomicron-like emulsions in subjects with atherogenic dyslipidemia: relevance to the in vivo metabolism of triglyceride-rich lipoproteins.
Delayed chylomicron clearance is a characteristic of patients with coronary artery disease. In vivo study of the clearance of labeled chylomicron-like emulsions constitutes a valid model system for evaluation of chylomicron catabolism. The effects of atorvastatin at low (10 mg) and high (40 mg) dose upon the intravascular metabolism and plasma kinetics of chylomicron-like emulsions were evaluated in fasting hyperlipidemic subjects (n=45). Subjects were randomized to a 6-week treatment period with placebo (n=15), low dose or high dose atorvastatin (10 mg/day, n=17 and 40 mg/day, n=13). The chylomicron-like emulsion, double-labeled with 14C-Cholesteryl oleate (14C-CE) and 3H-triolein (3H-TG), was injected in a bolus after a 12-h fast, and blood samples were collected up to 60 min. Plasma decay curves were determined for labeled emulsion CE and TG and residence times (RT) calculated by the occupancy principle. The 14C-CE RT was decreased by 50% after low dose atorvastatin and by 73% after atorvastatin at high dose in comparison to placebo (P<0.05). The 3H-TG RT was significantly reduced (-55%) after high dose atorvastatin, but in contrast was not significantly reduced after placebo or low dose statin. By compartmental analysis, both doses of atorvastatin led to marked elevation in the slow removal component of emulsion remnant particles (10 mg/day=107%; 40 mg/day=195%, P=0.01). Equally, the rapid removal component was increased (+99%) at high dose (P=0.015). Recirculation of 3H-fatty acids was significantly reduced at both statin doses (43 and 83%, respectively) in comparison to placebo (P=0.01). In conclusion, atorvastatin treatment accelerates the plasma clearance of chylomicron-like emulsions and reduces recirculation of fatty acids in subjects with atherogenic hyperlipidemia. Such effect might implicate in reduction of cardiovascular risk.
Sposito
Andrei C
AC
Heart Institute (InCor), University of São Paulo Medical School, Sao Paulo, Brazil.
Santos
Raul D
RD
Amâncio
Rosangela F
RF
Ramires
Jose A F
JA
Chapman
M John
MJ
Maranhão
Raul C
RC
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001161:Arteriosclerosis / Q000188:drug therapy / Q000473:pathology; D000069059:Atorvastatin; D008076:Cholesterol, HDL / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D002914:Chylomicrons / Q000097:blood / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005217:Fat Emulsions, Intravenous / Q000493:pharmacokinetics*; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage*; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000473:pathology; D000960:Hypolipidemic Agents / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D010316:Particle Size; D011336:Probability; D011758:Pyrroles / Q000008:administration & dosage*; D014280:Triglycerides / Q000378:metabolism
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D002914:Chylomicrons; D005217:Fat Emulsions, Intravenous; D006538:Heptanoic Acids; D000960:Hypolipidemic Agents; D011758:Pyrroles; D014280:Triglycerides; D000069059:Atorvastatin