Published online before print October 28, 2002, doi: 10.1161/01.CIR.0000038303.84249.4A
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(Circulation. 2002;106:2955.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Effect of Atorvastatin on High-Density Lipoprotein Apolipoprotein A-I Production and Clearance in the New Zealand White Rabbit
From the Department of Medicine, Division of Endocrinology (S.R., K.D.U., G.F.L.), and the Department of Physiology (P.H.R.B., G.F.L.), University of Toronto, Toronto, Canada; and the Department of Medicine, University of Western Australia, and the Western Australian Institute for Medical Research, Perth, Australia (P.H.R.B.).
Correspondence to Dr Gary Lewis, Toronto General Hospital, 200 Elizabeth St, Room EN11-229, Toronto, Ontario, Canada M5G 2C4. E-mail gary.lewis{at}uhn.on.ca
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.
Methods and 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 · kg-1 · d-1 (n=7) versus placebo-treated rabbits (n=7). Our results showed a significantly (P<0.001) more rapid clearance (
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 · kg-1 · 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.
Key Words: atorvastatin • hypercholesterolemia • apolipoproteins • lipoproteins
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