Transport mechanism of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors at the blood-brain barrier
Tsuji, A.; Saheki, A.; Tamai, I.; Terasaki, T.
Journal of Pharmacology and Experimental Therapeutics 267(3): 1085-1090
1993
ISSN/ISBN: 0022-3565 PMID: 8263769 Document Number: 419019
The transport mechanism of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors through the blood-brain barrier was studied in vitro by using primary cultures of bovine brain capillary endothelial cells (BCEC). The uptake of HMG-CoA reductase inhibitors with the lactone form, (14C)lovastatin and (14C)simvastatin, was slightly decreased to 65% of the control uptake (37 degree C) at low temperature (40 degree C) and was not affected by pretreatment of the BCEC with metabolic inhibitors (2,4-dinitrophenol and rotenone). (14C)Simvastatin acid (the lactone ringopened form) was taken up in a markedly temperature- and concentration-dependent fashion, whereas the uptake of (14C) pravastatin was negligible. At pH below 7.4, the uptake rate of (14C)simvastatin acid by the BCEC increased markedly with decreasing medium pH, whereas almost pH-independent uptake was observed in the presence of 1 mM simvastatin acid. Additional studies using an in situ rat brain perfusion method showed that the in vivo cerebrovascular permeation of (14C)simvastatin acid in rats was significantly inhibited in the presence of 1 mM simvastatin acid, demonstrating that the transport system for the acid forms of HMG-CoA reductase inhibitors functions under in vivo conditions. Several monocarboxylic acids significantly inhibited the uptake of (14C)simvastatin acid by the BCEC, whereas dicarboxylic acids did not. The uptake of (14C)simvastatin acid by the BCEC was competitively inhibited by 15 mM acetic acid. Accordingly, we concluded that HMG-CoA reductase inhibitors in lactone form are transported via simple diffusion, whereas those having an acid form are transported across the blood-brain barrier via a carrier-mediated transport mechanism for monocarboxylic acids. Negligible transport of pravastatin was ascribed to its hydrophilicity and low affinity to the transporter in the blood-brain barrier.