Published Online
on October 28, 2002

A more recent version of this article appeared on December 3, 2002

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Submitted on June 26, 2002
Revised on August 27, 2002
Accepted on August 27, 2002

Effect of Atorvastatin on High-Density Lipoprotein Apolipoprotein A-I Production and Clearance in the New Zealand White Rabbit

Shirya Rashid MSc, Kristine D. Uffelman BSc, P. Hugh R. Barrett PhD, and Gary F. Lewis MD, FRCP(C)^*

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.).

^* To whom correspondence should be addressed. 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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