Effect of atorvastatin on high-density lipoprotein apolipoprotein A-I production and clearance in the New Zealand white rabbit.
BACKGROUND
HMG-CoA reductase inhibitors reduce the incidence of cardiovascular disease predominantly by their LDL-lowering effect. Recently, there has been great interest in the pleiotropic effects of statins, which appear to differ among the various agents in this class. Unlike other statins, atorvastatin exhibits a decline in its HDL-raising effect at higher doses in humans. Whether atorvastatin-mediated alterations in HDL turnover in vivo contribute to this effect has not previously been investigated. We therefore studied the effect of atorvastatin on HDL apolipoprotein (apo) A-I production and clearance in normolipidemic male New Zealand White rabbits.


RESULTS
Kinetic studies of HDL-apoA-I radiolabeled with 131I were performed in chow-fed rabbits after 3 weeks of atorvastatin treatment of 5 mg x kg(-1) x d(-1) (n=7) versus placebo-treated rabbits (n=7). Our results showed a significantly (P<0.001) more rapid clearance ( approximately 2-fold) of HDL apoA-I in atorvastatin-treated animals compared with the control group (0.121+/-0.012 versus 0.061+/-0.004 pools/h, respectively), accompanied by a lesser 48% increase in the apoA-I production rate (3.84+/-0.38 versus 2.59+/-0.41 mg x kg(-1) x h(-1), P=0.06). Accordingly, plasma apoA-I levels in atorvastatin-treated animals declined significantly (P<0.05, n=8 animals) after 3 weeks of treatment (173.5+/-1.8 mg/dL) from baseline values.


CONCLUSIONS
These data suggest that the effect on apoA-I levels observed with atorvastatin at higher drug doses in humans may be caused at least in part by enhanced HDL apoA-I catabolism, which is not entirely offset by a concomitant increase in apoA-I production. Whether this finding results from an effect of atorvastatin on HDL particle composition or on receptors involved in circulating HDL holoparticle clearance will require further study.
Rashid
Shirya
S
Department of Medicine, Division of Endocrinology, University of Toronto, Toronto, Canada.
Uffelman
Kristine D
KD
Barrett
P Hugh R
PH
Lewis
Gary F
GF
D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D000069059:Atorvastatin; D002784:Cholesterol / Q000097:blood; D002788:Cholesterol Esters / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007457:Iodine Radioisotopes; D008075:Lipoproteins, HDL / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D023421:Models, Animal; D010743:Phospholipids / Q000097:blood; D011758:Pyrroles / Q000494:pharmacology*; D011817:Rabbits; D011849:Radioactive Tracers; D014280:Triglycerides / Q000097:blood
D016632:Apolipoprotein A-I; D002788:Cholesterol Esters; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007457:Iodine Radioisotopes; D008075:Lipoproteins, HDL; D010743:Phospholipids; D011758:Pyrroles; D011849:Radioactive Tracers; D014280:Triglycerides; D002784:Cholesterol; D000069059:Atorvastatin