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 degrees C) at low temperature (4 degrees C) and was not affected by pretreatment of the BCEC with metabolic inhibitors (2,4-dinitrophenol and rotenone). [14C]Simvastatin acid (the lactone ring-opened 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.(ABSTRACT TRUNCATED AT 250 WORDS)