Masaru Hirano

The University of Tokyo, Edo, Tōkyō, Japan

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Publications (10)45.75 Total impact

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    ABSTRACT: The objective is to confirm if the prediction of the drug-drug interaction using a physiologically based pharmacokinetic (PBPK) model is more accurate. In vivo Ki values were estimated using PBPK model to confirm whether in vitro Ki values are suitable. The plasma concentration-time profiles for the substrate with coadministration of an inhibitor were collected from the literature and were fitted to the PBPK model to estimate the in vivo Ki values. The AUC ratios predicted by the PBPK model using in vivo Ki values were compared with those by the conventional method assuming constant inhibitor concentration. The in vivo Ki values of 11 inhibitors were estimated. When the in vivo Ki values became relatively lower, the in vitro Ki values were overestimated. This discrepancy between in vitro and in vivo Ki values became larger with an increase in lipophilicity. The prediction from the PBPK model involving the time profile of the inhibitor concentration was more accurate than the prediction by the conventional methods. A discrepancy between the in vivo and in vitro Ki values was observed. The prediction using in vivo Ki values and the PBPK model was more accurate than the conventional methods.
    Pharmaceutical Research 09/2008; 25(8):1891-901. DOI:10.1007/s11095-008-9607-2 · 3.42 Impact Factor
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    ABSTRACT: To investigate the contribution of genetic polymorphisms of SLCO1B1 and ABCG2 to the pharmacokinetics of a dual substrate, pitavastatin, 2 mg of pitavastatin was administered to 38 healthy volunteers and pharmacokinetic parameters were compared among the following groups: 421C/C(*)1b/(*)1b (group 1), 421C/C(*)1b/(*)15 (group 2), 421C/C(*)15/(*)15 and 421C/A(*)15/(*)15 (group 3), 421C/A(*)1b/(*)1b (group 4), 421A/A(*)1b/(*)1b (group 5), and 421C/A(*)1b/(*)15 (group 6). In SLCO1B1, pitavastatin area under plasma concentration-time curve from 0 to 24 h (AUC(0-24)) for groups 1, 2, and 3 was 81.1+/-18.1, 144+/-32, and 250+/-57 ng h/ml, respectively, with significant differences among all three groups. In contrast to SLCO1B1, AUC(0-24) in groups 1, 4, and 5 was 81.1+/-18.1, 96.7+/-35.4, and 78.2+/-8.2 ng h/ml, respectively. Although the SLCO1B1 polymorphism was found to have a significant effect on the pharmacokinetics of pitavastatin, a nonsynonymous ABCG2 variant, 421C>A, did not appear to be associated with the altered pharmacokinetics of pitavastatin.
    Clinical Pharmacology &#38 Therapeutics 11/2007; 82(5):541-7. DOI:10.1038/sj.clpt.6100190 · 7.90 Impact Factor
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    Masaru Hirano · Kazuya Maeda · Yoshihisa Shitara · Yuichi Sugiyama ·
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    ABSTRACT: It has already been demonstrated that pitavastatin, a novel potent HMG-coenzyme A reductase inhibitor, is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP) 1B1. Because OATP2B1 is also localized in the basolateral membrane of human liver, we took two approaches to further confirm the minor contribution of OATP2B1 to the hepatic uptake of pitavastatin. Western blot analysis revealed that the ratio of the band density of OATP2B1 in human hepatocytes to that in our expression system is at least 6-fold lower compared with OATP1B1 and OATP1B3. The uptake of pitavastatin in human hepatocytes could be inhibited by both estrone-3-sulfate (OATP1B1/OATP2B1 inhibitor) and estradiol-17beta-D-glucuronide (OATP1B1/OATP1B3 inhibitor). These results further supported the idea that OATP1B1 is a predominant transporter for the hepatic uptake of pitavastatin. Then, to explore the possibility of OATP1B1-mediated drug-drug interaction, we checked the inhibitory effects of various drugs on the pitavastatin uptake in OATP1B1-expressing cells and evaluated whether the in vitro inhibition was clinically significant or not. As we previously reported, we used the methodology for estimating the maximum unbound concentration of inhibitors at the inlet to the liver (I(u,in,max)). Judging from I(u,in,max) and inhibition constant (K(i)) for OATP1B1, several drugs (especially cyclosporin A, rifampicin, rifamycin SV, clarithromycin, and indinavir) have potentials for interacting with OATP1B1-mediated uptake of pitavastatin. The in vitro experiments could support the clinically observed drug-drug interaction between pitavastatin and cyclosporin A. These results suggest that we should pay attention to the concomitant use of some drugs with pitavastatin.
    Drug Metabolism and Disposition 08/2006; 34(7):1229-36. DOI:10.1124/dmd.106.009290 · 3.25 Impact Factor
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    ABSTRACT: Recent reports have shown that genetic polymorphisms in organic anion transporting polypeptide (OATP) 1B1 have an effect on the pharmacokinetics of drugs. However, the impact of OATP1B1*1b alleles, the frequency of which is high in all ethnicities, on the pharmacokinetics of substrate drugs is not known after complete separation of subjects with OATP1B1*1a and *1b. Furthermore, the correlation between the clearances of OATP1B1 substrate drugs in individuals has not been characterized. We investigated the effect of genetic polymorphism of OATP1B1, particularly the *1b allele, on the pharmacokinetics of 3 anionic drugs, pravastatin, valsartan, and temocapril, in Japanese subjects. Twenty-three healthy Japanese volunteers were enrolled in a 3-period crossover study. In each period, after a single oral administration of pravastatin, valsartan, or temocapril, plasma and urine were collected for up to 24 hours. The area under the plasma concentration-time curve (AUC) of pravastatin in *1b/*1b carriers (47.4 +/- 19.9 ng.h/mL) was 65% of that in *1a/*1a carriers (73.2 +/- 23.5 ng.h/mL) (P = .049). Carriers of *1b/*15 (38.2 +/- 15.9 ng.h/mL) exhibited a 45% lower AUC than *1a/*15 carriers (69.2 +/- 23.4 ng.h/mL) (P = .024). In the case of valsartan we observed a similar trend as with pravastatin, although the difference was not statistically significant (9.01 +/- 3.33 microg.h/mL for *1b/*1b carriers versus 12.3 +/- 4.6 microg.h/mL for *1a/*1a carriers [P = .171] and 6.31 +/- 3.64 microg.h/mL for *1b/*15 carriers versus 9.40 +/- 4.34 microg.h/mL for *1a/*15 carriers [P = .213]). The AUC of temocapril also showed a similar trend (12.4 +/- 4.1 ng.h/mL for *1b/*1b carriers versus 18.5 +/- 7.7 ng.h/mL for *1a/*1a carriers [P = .061] and 16.4 +/- 5.0 ng.h/mL for *1b/*15 carriers versus 19.0 +/- 4.1 ng.h/mL for *1a/*15 carriers [P = .425]), whereas that of temocaprilat (active form of temocapril) was not significantly affected by the haplotype of OATP1B1. Interestingly, the AUC of valsartan and temocapril in each subject was significantly correlated with that of pravastatin (R = 0.630 and 0.602, P < .01). The renal clearance remained unchanged for each haplotype for all drugs. The major clearance mechanism of pravastatin, valsartan, and temocapril appears to be similar, and OATP1B1*1b is one of the determinant factors governing the interindividual variability in the pharmacokinetics of pravastatin and, possibly, valsartan and temocapril.
    Clinical Pharmacology &#38 Therapeutics 05/2006; 79(5):427-39. DOI:10.1016/j.clpt.2006.01.011 · 7.90 Impact Factor
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    ABSTRACT: Until recently, it was generally believed that the transport of various organic anions across the bile canalicular membrane was mainly mediated by multidrug resistance-associated protein 2 (MRP2/ABCC2). However, a number of new reports have shown that some organic anions are also substrates of multidrug resistance 1 (MDR1/ABCB1) and/or breast cancer resistance protein (BCRP/ABCG2), implying MDR1 and BCRP could also be involved in the biliary excretion of organic anions in humans. In the present study, we constructed new double-transfected Madin-Darby canine kidney II (MDCKII) cells expressing organic anion-transporting polypeptide 1B1 (OATP1B1)/MDR1 and OATP1B1/BCRP, and we investigated the transcellular transport of four kinds of organic anions, estradiol-17beta-d-glucuronide (EG), estrone-3-sulfate (ES), pravastatin (PRA), and cerivastatin (CER), to identify which efflux transporters mediate the biliary excretion of compounds using double-transfected cells. We observed the vectorial transport of EG and ES in all the double transfectants. MRP2 showed the highest efflux clearance of EG among these efflux transporters, whereas BCRP-mediated clearance of ES was the highest in these double transfectants. In addition, two kinds of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, CER and PRA, were also substrates of all these efflux transporters. The rank order of the efflux clearance of PRA mediated by each transporter was the same as that of EG, whereas the contribution of MDR1 to the efflux of CER was relatively greater than for PRA. This experimental system is very useful for identifying which transporters are involved in the biliary excretion of organic anions that cannot easily penetrate the plasma membrane.
    Journal of Pharmacology and Experimental Therapeutics 10/2005; 314(3):1059-67. DOI:10.1124/jpet.105.085589 · 3.97 Impact Factor
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    ABSTRACT: Pitavastatin, a novel potent 3-hydroxymethylglutaryl coenzyme A reductase inhibitor, is distributed selectively to the liver and excreted into bile in unchanged form in rats. We reported previously that the hepatic uptake is mainly mediated by organic anion transporting polypeptide (OATP) 1B1, whereas the biliary excretion mechanism remains to be clarified. In the present study, we investigated the role of breast cancer resistance protein (BCRP) in the biliary excretion of pitavastatin. The ATP-dependent uptake of pitavastatin by human and mouse BCRP-expressing membrane vesicles was significantly higher compared with that by control vesicles with Km values of 5.73 and 4.77 microM, respectively. The biliary excretion clearance of pitavastatin in Bcrp1-/- mice was decreased to one-tenth of that in control mice. The biliary excretion of pitavastatin was unchanged between control and Eisai hyperbilirubinemic rats, indicating a minor contribution of multidrug resistance-associated protein (Mrp) 2. This observation differs radically from that for a more hydrophilic statin, pravastatin, of which biliary excretion is largely mediated by Mrp2. These data suggest that the biliary clearance of pitavastatin can be largely accounted for by BCRP in mice. In the case of humans, transcellular transport of pitavastatin was determined in the Madin-Darby canine kidney II cells expressing OATP1B1 and human canalicular efflux transporters. A significant basal-to-apical transport of pitavastatin was observed in OATP1B1/MDR1 and OATP1B1/MRP2 double transfectants as well as OATP1B1/BCRP double transfectants, implying the involvement of multiple transporters in the biliary excretion of pitavastatin in humans. This is in contrast to a previous belief that the biliary excretion of statins is mediated mainly by MRP2.
    Molecular Pharmacology 10/2005; 68(3):800-7. DOI:10.1124/mol.105.014019 · 4.13 Impact Factor
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    ABSTRACT: Pravastatin is a well known 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor. Cumulative studies have shown that pravastatin is taken up into hepatocytes by the organic anion transporting polypeptide family transporters and excreted into the bile as an intact form by multidrug resistance-associated protein 2 (MRP2). It is generally accepted that the bile salt export pump (BSEP/ABCB11) mainly transports bile acids and plays an indispensable role in their biliary excretion. Interestingly, we found that BSEP could accept pravastatin as a substrate. Significant ATP-dependent uptake of pravastatin by human BSEP (hBSEP)- and rat BSEP (rBsep)-expressing membrane vesicles was observed, and the ratio of the uptake activity of pravastatin to that of taurocholic acid (TCA) by hBSEP was 3.3-fold higher than that by rBsep. The K(m) value of pravastatin for hBSEP was 124 muM. A mutual inhibition study between TCA and pravastatin revealed that they competitively interact with hBSEP. Several statins inhibited the hBSEP- and rBsep-mediated uptake of TCA; however, the specific uptake of other statins (cerivastatin, fluvastatin, and pitavastatin) by hBSEP and rBSEP was not detected. The inhibitory effects of hydrophilic statins (pravastatin and rosuvastatin) on the uptake of TCA by BSEP were relatively lower than those of lipophilic statins. These data suggest that BSEP may be partly involved in the biliary excretion of pravastatin in both rats and humans.
    Journal of Pharmacology and Experimental Therapeutics 09/2005; 314(2):876-82. DOI:10.1124/jpet.105.084830 · 3.97 Impact Factor
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    ABSTRACT: Previously, we have shown that the inhibition of the transporter-mediated hepatic uptake of cerivastatin (CER) by cyclosporin A (CsA) could, at least partly, explain a pharmacokinetic interaction between these drugs in humans. In the present study, we have examined the effect of CsA on the in vivo disposition of CER in rats and the in vitro uptake of [14C]CER in isolated rat hepatocytes in an attempt to evaluate the effect of inhibition of transporter-mediated hepatic uptake on the in vivo CER disposition. The steady-state plasma concentration of CER increased 1.4-fold when coadministered with CsA up to a steady-state blood concentration of 4 microM. Studies of [14C]CER uptake into isolated rat hepatocytes showed saturable transport, with the saturable portion accounting for more than 80% of the total uptake. CsA competitively inhibited the uptake of [14C]CER with a Ki of 0.3 microM. The IC50 for the uptake of [14C]CER in the absence and presence of rat plasma was 0.2 and 2.3 microM, respectively. The in vivo hepatic uptake of [14C]CER evaluated by the liver uptake index method was also inhibited by CsA in a dose-dependent manner. On the other hand, CsA did not inhibit the metabolism of [14C]CER in rat microsomes. The in vitro and in vivo correlation analysis revealed that this pharmacokinetic interaction between these drugs in rats could be quantitatively explained by the inhibition of transporter-mediated hepatic uptake. Thus, this drug-drug interaction in rats is predominantly caused by the transporter-mediated uptake process.
    Drug Metabolism and Disposition 01/2005; 32(12):1468-75. · 3.25 Impact Factor
  • Masaru Hirano · Kazuya Maeda · Yoshihisa Shitara · Yuichi Sugiyama ·
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    ABSTRACT: Pitavastatin, a novel potent 3-hydroxymethylglutaryl-CoA reductase inhibitor, is selectively distributed to the liver in rats. However, the hepatic uptake mechanism of pitavastatin has not been clarified yet. In the present study, we investigated the contribution of organic anion transporting polypeptide 2 (OATP2/OATP1B1) and OATP8 (OATP1B3) to pitavastatin uptake using transporter-expressing HEK293 cells and human cryopreserved hepatocytes. Uptake studies using OATP2- and OATP8-expressing cells revealed a saturable and Na(+)-independent uptake, with K(m) values of 3.0 and 3.3 microM for OATP2 and OATP8, respectively. To determine which transporter is more important for its hepatic uptake, we proposed a methodology for estimating their quantitative contribution to the overall hepatic uptake by comparing the uptake clearance of pitavastatin with that of reference compounds (a selective substrate for OATP2 (estrone-3-sulfate) and OATP8 (cholecystokinin octapeptide) in expression systems and human hepatocytes. The concept of this method is similar to the so-called relative activity factor method often used in estimating the contribution of each cytochrome P450 isoform to the overall metabolism. Applying this method to pitavastatin, the observed uptake clearance in human hepatocytes could be almost completely accounted for by OATP2 and OATP8, and about 90% of the total hepatic clearance could be accounted for by OATP2. This result was also supported by estimating the relative expression level of each transporter in expression systems and hepatocytes by Western blot analysis. These results suggest that OATP2 is the most important transporter for the hepatic uptake of pitavastatin in humans.
    Journal of Pharmacology and Experimental Therapeutics 11/2004; 311(1):139-46. DOI:10.1124/jpet.104.068056 · 3.97 Impact Factor
  • Yoshihisa Shitara · Masaru Hirano · Hitoshi Sato · Yuichi Sugiyama ·
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    ABSTRACT: A serious pharmacokinetic interaction between cerivastatin (CER) and gemfibrozil (GEM) has been reported. In the present study, we examined the inhibitory effects of GEM and its metabolites, M3 and gemfibrozil 1-O-beta-glucuronide (GEM-1-O-glu), on the uptake of CER by human organic anion transporting polypeptide 2 (OATP2)-expressing cells and its metabolism in cytochrome P450 expression systems. Uptake studies showed that GEM and GEM-1-O-glu significantly inhibited the OATP2-mediated uptake of CER with IC(50) values of 72 and 24 microM, respectively. They also inhibited the CYP2C8-mediated metabolism of CER with IC(50) values of 28 and 4 microM, respectively, whereas M3 had no effects. GEM and GEM-1-O-glu minimally inhibited the CYP3A4-mediated metabolism of CER. The IC(50) values of GEM and GEM-1-O-glu for the uptake and the metabolism of CER obtained in the present study were lower than their total, and not unbound, plasma concentrations. However, considering the possibly concentrated high unbound concentrations of GEM-1-O-glu in the liver and its relatively larger plasma unbound fraction compared with GEM itself, the glucuronide inhibition of the CYP2C8-mediated metabolism of CER appears to be the main mechanism for the clinically relevant drug-drug interaction. Previously reported clinical drug interaction studies showing that coadministration of GEM with pravastatin or pitavastatin, both of which are known to be cleared from the plasma by the uptake transporters in the liver, only minimally (less than 2-fold) increased the area under the plasma concentration-time curve of these statins, also supported our present conclusion.
    Journal of Pharmacology and Experimental Therapeutics 11/2004; 311(1):228-36. DOI:10.1124/jpet.104.068536 · 3.97 Impact Factor