Involvement of Multiple Transporters in the Efflux of 3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitors across the Blood-Brain Barrier

Abstract

Statins, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, are frequently used for the treatment of hypercholesterolemia. The present study aimed to examine the involvement of organic anion transporters in the efflux transport of pravastatin and pitavastatin across the blood-brain barrier (BBB). Transport studies using cDNA-transfected cells revealed that these statins are substrates of multispecific organic anion transporters expressed at the BBB (rOat3:Slc22a8 and rOatp2:Slco1a4). The efflux of these statins across the BBB was characterized using the brain efflux index method. The efflux clearance of pitavastatin across the BBB, obtained from the elimination rate constant and the distribution volume in the brain, was greater than that of pravastatin (364 versus 59 l/min/g brain). The efflux of pravastatin and pitavastatin was saturable (apparent K m values:18 and 5 M, respectively) and inhibited by probenecid but unaffected by tetraethylammonium. Furthermore, an inhibitor of the efflux pathway for hydrophilic organic anions across the BBB (p-aminohippurate), and inhibitors of the efflux pathway for amphipathic organic anions (taurocholate and digoxin) inhibited the efflux of both statins. The degree of inhibition by p-aminohippurate was similar and partial for the efflux of pravastatin and pitavastatin. Taurocholate and digoxin completely inhibited the efflux of pitavastatin, whereas their effect was partial for the efflux of pravastatin. The results of the present study suggest the involvement of multiple transporters, including rOat3 and rOatp2, in the efflux transport of pravastatin and pitavastatin across the BBB, each making a different contribution.

Solute Carrier Family of the Organic Anion-Transporting Polypeptides 1A2– Madin-Darby Canine Kidney II: A Promising In Vitro System to Understand the Role of Organic Anion-Transporting Polypeptide 1A2 in Blood-Brain Barrier Drug Penetration

“…Unlike OATP1A2, Oapt1a4 is expressed at both the apical and basolateral membranes of the microvascular endothelium of the BBB (Gao et al, 1999;Ose et al, 2010). Oatp1a4 has a wide substrate spectrum that includes amphipathic organic anions, such as 17b-estradiol-17b-D-glucuronide (E 2 17bG) and statins (Kikuchi et al, 2004), prostaglandin E1 (Taogoshi et al, 2005), and morphine-6-glucuronide (Bourasset et al, 2003). Oatp1a4 functional expression at the rat BBB increases with pain and correlates with taurocholate transport across the BBB (Ronaldson et al, 2011).…”

Nonclinical Pharmacokinetics of Oseltamivir and Oseltamivir Carboxylate in the Central Nervous System

“…All three transporters are expressed in the BBB (11,12,25) and could theoretically contribute to the active transport of OC out of the brain. A functional role for MRP4 was suggested by the finding that in Mrp4 knockout mice, the exposure of OC in brain was fourfold higher than that in wild-type animals (23).…”

Limited Brain Distribution of [3R,4R,5S]-4-Acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate Phosphate (Ro 64-0802), a Pharmacologically Active Form of Oseltamivir, by Active Efflux across the Blood-Brain Barrier Mediated by Organic Anion Transporter 3 (Oat3/Slc22a8) and Multidrug Resistance-Associated Protein 4 (Mrp4/Abcc4)

“…Oat3 is expressed on the abluminal membrane of the brain capillary endothelial cells in rodents (Kikuchi et al, 2003;Mori et al, 2003;Roberts et al, 2008). Cumulative in vivo studies suggest that Oat3 plays a significant role in the uptake of hydrophilic organic anions into the endothelial cells, the first step in its overall elimination from the brain to the blood (Ohtsuki et al, 2002;Kikuchi et al, 2003Kikuchi et al, , 2004Mori et al, 2003Mori et al, , 2004. Ro 64-0802 has been identified as a substrate of OAT1/ SLC22A6 (Hill et al, 2002).…”