Pravastatin, an HMG-CoA Reductase Inhibitor, is Transported by Rat Organic Anion Transporting Polypeptide, oatp2

Tokui, Taro; Nakai, Daisuke; Nakagomi, Rie; Kakyo, Masayuki; Nishio, Takeshi; Abe, Takaaki; Suzuki, Hiroshi; Sugiyama, Yuichi

doi:10.1007/978-4-431-68424-4_37

Cited by 34 publications

(51 citation statements)

References 2 publications

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“…Time course to determine the maximal expression of Oatp2 mRNA during the 4-day PCN treatment paradigm. PCN was administered (75 mg/kg/d) intraperitoneally for 4 consecutive days, and livers were removed at various time points (6,12,24,36,48,72, and 96 hours) after the initial dose. Vehicle-treated control animals received corn oil, and livers were removed at 24 and 72 hours.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of Microsomal Enzyme-Inducing Chemicals on the Hepatic Expression of Rat Organic Anion Transporters, Oatp1 and Oatp2

Rausch‐Derra

2001

Hepatology

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The organic anion transporting polypeptides, Oatp1 (Slc21a1) and Oatp2 (Slc21a5), mediate hepatic uptake of cardiac glycosides. Previously, we demonstrated that chemicals that increase cytochrome P450s differentially affect hepatic uptake of cardiac glycosides. We postulated that increased uptake of cardiac glycosides observed after pretreatment of animals with phenobarbital (PB) and pregnenolone-16␣-carbonitrile ( Hepatic clearance and biliary excretion of drugs and their metabolites can occur through passive transport or through active transport (carrier-mediated) systems. Previous studies from this laboratory described a phenomenon in which pretreatment of animals with chemicals known to differentially increase specific microsomal cytochrome P450 enzymes also enhanced both hepatic plasma clearance and biliary excretion of a number of choleophiles, including cardiac glycosides. [1][2][3][4] Specifically, pretreatment of rats with two compounds known classically to activate CYP2B and CYP3A transcription, the barbiturate phenobarbital (PB) and the synthetic steroid pregenenolone-16␣-carbonitrile (PCN), respectively, resulted in the decreased plasma half-life, increased hepatic clearance, and decreased toxicity of cardiac glycosides. In contrast, pretreatment of rats with chemicals known to act through the aryl hydrocarbon receptor resulted in a slight suppression of cardiac glycoside plasma clearance by the liver. 2 Further studies demonstrated that PCN increased the maximal velocity and affinity of ouabain uptake into hepatocytes, 3 suggesting that this chemical altered the hepatocellular capacity and affinity for choleophilic substrates. In subsequent studies, an energydependent, Na ϩ -independent carrier-mediated transport system for ouabain was identified. This Na ϩ -independent transport system was sensitive to inhibition by neutral (e.g., digoxin), acidic (e.g., taurocholate), and basic (e.g., quinine) compounds. 4 Together, these findings suggested that a multispecific, Na ϩ -independent hepatic transport system existed, which could be positively modulated by microsomal enzymeinducing chemicals, specifically PB and PCN.Since these earlier reports, 1-4 specific mediators of this hepatic Na ϩ -independent transport system have been cloned and characterized, and consist of several members of the rat organic anion transporting polypeptide (Oatp) family. The primary forms expressed in rat liver include, Oatp1 (gene symbol: Slc21a1), Oatp2 (Slc21a5), and liver-specific transporter 1 (rlst-1) or Oatp4 (Slc21a10). In rat liver, the organic anion transporting polypeptides, Oatp1, 5 Oatp2, 6,7 and rlst-1/ Oatp4, 8-10 transport a number of conjugated and unconjugated xenobiotics and endobiotics in a charge-independent manner. The substrates for this family of transporters include: the cardiac glycosides, the statin class of lipid-lowering drugs, human immunodeficiency virus-protease inhibitors, bile acids, eicosanoids, thyroid hormone and thyroid hormone conjugates, steroid hormone conjugates, and numerous peptidede...

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Section: Discussionmentioning

confidence: 99%

Differential Effects of Microsomal Enzyme-Inducing Chemicals on the Hepatic Expression of Rat Organic Anion Transporters, Oatp1 and Oatp2

Rausch‐Derra

2001

Hepatology

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“…These results are comparable with the previous report (Hoffmaster et al, 2004) and support our results in which the saturable uptake of digoxin, an Oatp1a4-selective substrate, was drastically decreased in 96-h-cultured SCRH. Oatp1b2 expression was also largely decreased after long-term culture, whereas uptake activity of pravastatin was well preserved, which suggests that pravastatin uptake into hepatocytes is dominated not only by Oatp1b2 but also by Oatp1a1 (Hsiang et al, 1999) and Oatp1a4 (Tokui et al, 1999).…”

Section: Uptake Activity In Sandwich-cultured Hepatocytesmentioning

confidence: 94%

Culture Period-Dependent Changes in the Uptake of Transporter Substrates in Sandwich-Cultured Rat and Human Hepatocytes

Kotani

Maeda²,

Watanabe³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Sandwich-cultured hepatocytes (SCH) are a useful tool for evaluating hepatobiliary drug transport in vitro. Some studies have investigated the in vitro-in vivo correlations of the biliary clearance of drugs using SCH. In most cases, the biliary clearance observed in vivo correlated well with the predicted clearance, but the predicted absolute values were underestimated when based on in vitro experiments with SCH. We hypothesized that the down-regulated function of uptake transporters is one of the causes of this underestimation. Therefore, the uptake of taurocholate, digoxin, pravastatin, and rosuvastatin was investigated in sandwich-cultured rat hepatocytes (SCRH) cultured for 5, 24, 48, and 96 h, and the predicted hepatic clearance from in vitro uptake clearance (CL H, vitro ) was calculated with a dispersion model. In SCRH cultured for 96 h, the saturable uptake of taurocholate, digoxin, pravastatin, and rosuvastatin decreased to 7.5, 3.3, 64, and 23%, respectively, of their uptake in hepatocytes cultured for 5 h, and a better prediction of in vivo hepatic clearance (CL H, vivo ) was achieved when based on CL H, vitro of 5-h-cultured hepatocytes. These results suggest that the uptake activity is considerably reduced in cell culture, even in a sandwich-culture format. In a similar study, we also examined taurocholate and rosuvastatin in sandwich-cultured human hepatocytes (SCHH). Unlike in SCRH, the saturable uptake of these compounds did not differ markedly in SCHH cultured for 5 or 96 h. Thus, the uptake activity in SCHH was maintained relatively well compared with that in SCRH.

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“…rOatp2, another multispecific organic anion transporter expressed at the BBB (Gao et al, 1999), has been suggested to account for the efflux of amphipathic organic anions across the BBB Hosoya et al, 2000;Sugiyama et al, 2001). Since pravastatin is a substrate of both rOat3 and rOatp2 (Tokui et al, 1999;Hasegawa et al, 2002), these transporters may be involved in the efflux of pravastatin and, possibly, of pitavastatin, from the brain across the BBB, accounting for the lower brain distribution of pitavastatin compared with that of pravastatin.…”

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confidence: 99%

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

Kikuchi¹,

Kusuhara²,

Abe³

et al. 2004

J Pharmacol Exp Ther

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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.

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Pravastatin, an HMG-CoA Reductase Inhibitor, is Transported by Rat Organic Anion Transporting Polypeptide, oatp2

Cited by 34 publications

References 2 publications

Differential Effects of Microsomal Enzyme-Inducing Chemicals on the Hepatic Expression of Rat Organic Anion Transporters, Oatp1 and Oatp2

Differential Effects of Microsomal Enzyme-Inducing Chemicals on the Hepatic Expression of Rat Organic Anion Transporters, Oatp1 and Oatp2

Culture Period-Dependent Changes in the Uptake of Transporter Substrates in Sandwich-Cultured Rat and Human Hepatocytes

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

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