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

Abstract

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 131 I 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.