Transport mechanism of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors at the blood-brain barrier.
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)
Tsuji
A
A
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
Saheki
A
A
Tamai
I
I
Terasaki
T
T
D000085:Acetates / Q000493:pharmacokinetics; D019342:Acetic Acid; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D010477:Perfusion; D017035:Pravastatin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D019821:Simvastatin / Q000031:analogs & derivatives; D013696:Temperature
D000085:Acetates; D002250:Carbon Radioisotopes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C063287:simvastatin acid; D008148:Lovastatin; D019821:Simvastatin; D017035:Pravastatin; D019342:Acetic Acid