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Bruno Hagenbuch - One of the best experts on this subject based on the ideXlab platform.

  • Cysteine scanning mutagenesis of transmembrane domain 10 in Organic anion transporting Polypeptide 1B1.
    Biochemistry, 2014
    Co-Authors: Shuichi Ohnishi, Amanda Hays, Bruno Hagenbuch
    Abstract:

    Organic anion transporting Polypeptide (OATP) 1B1 is an important drug transporter expressed in human hepatocytes. Previous studies have indicated that transmembrane (TM) domain 2, 6, 8, 9, and in particular 10 might be part of the substrate binding site/translocation pathway. To explore which amino acids in TM10 are important for substrate transport, we mutated 34 amino acids individually to cysteines, expressed them in HEK293 cells, and determined their surface expression. Transport activity of the two model substrates estrone-3-sulfate and estradiol-17β-glucuronide as well as of the drug substrate valsartan for selected mutants was measured. Except for F534C and F537C, all mutants were expressed at the plasma membrane of HEK293 cells. Mutants Q541C and A549C did not transport estradiol-17β-glucuronide and showed negligible estrone-3-sulfate transport. However, A549C showed normal valsartan transport. Pretreatment with the anionic and cell impermeable sodium (2-sulfonatoethyl)methanethiosulfonate (MTSES...

  • Organic anion transporting Polypeptide 1B3 can form homodimers (1064.17)
    The FASEB Journal, 2014
    Co-Authors: Yuchen Zhang, Bruno Hagenbuch
    Abstract:

    Organic Anion Transporting Polypeptide 1B3 (OATP1B3) is under normal physiological conditions mainly expressed at basolateral membrane of human hepatocytes where it is thought to mediate uptake of ...

  • Abstract 812: Identification of novel anticancer drugs as substrates of Organic anion transporting Polypeptide 1B3 using a cell viability assay
    Cancer Research, 2012
    Co-Authors: Amanda L. Obaidat-hays, Bruno Hagenbuch
    Abstract:

    Organic anion transporting Polypeptide 1B3 (OATP1B3) belongs to a superfamily of transport proteins that mediate the uptake of a wide range of endogenous and exogenous compounds into cells. Under normal conditions OATP1B3 is selectively expressed at the basolateral membrane of human hepatocytes. Recently, OATP1B3 expression has been detected in a variety of different cancers and because of its multispecificity OATP1B3 is thought to be a potential therapeutic target to enhance drug delivery into cancer cells. Thus far, only a few anticancer drugs have been identified as substrates of OATP1B3 including docetaxel, paclitaxel, methotrexate and imatinib. Given that OATP1B3 can potentially be used as a target for anticancer drug delivery we need to identify additional anticancer drug substrates of OATP1B3. Therefore, we aimed at establishing a cell based high throughput assay to screen the NCI approved oncology drug set for novel cytotoxic substrates of OATP1B3. Using a luminescent cell viability assay, we measured the viability of wild-type and OATP1B3-expressing Chinese Hamster Ovary (CHO) cells in the absence or presence of the anticancer drugs. After we identified positive hits we further characterized them with respect to concentration dependencies. We identified etoposide, bleomycin, oxaliplatin and plicamycin as compounds that kill OATP1B3-expressing CHO cells at much lower concentrations than wild-type CHO cells suggesting that these compounds are substrates of OATP1B3. Using secondary assays we confirmed that etoposide is a substrate of OATP1B3 and we are currently testing the remaining compounds for direct uptake by OATP1B3. In conclusion, this cell-based viability assay is a good tool to identify novel cytotoxic OATP1B3 substrates that can potentially be used to treat OATP1B3-expressing cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 812. doi:1538-7445.AM2012-812

  • Cloning/characterization of the canine Organic anion transporting Polypeptide 1b4 (Oatp1b4) and classification of the canine OATP/SLCO members.
    Comparative Biochemistry and Physiology C-toxicology & Pharmacology, 2010
    Co-Authors: Bruno Hagenbuch
    Abstract:

    Abstract The human liver-specific Organic anion transporting Polypeptides (OATPs) 1B1 and 1B3 are involved in the elimination of numerous xenobiotics and drugs. Although dogs are frequently used for toxicologic and pharmacokinetic characterization of novel drugs, nothing is known about their OATP1B1/1B3 ortholog. Therefore, we cloned and characterized the first canine Organic anion transporting Polypeptide from dog liver, termed Oatp1b4. The isolated Oatp1b4 cDNA comprises 3661 base pairs (bp) with an open reading frame of 2076 bp, encoding a 692-amino acid protein with a molecular mass of ∼ 85 kDa. The Oatp1b4 gene is approximately 61 kb long and has a similar organization as the human OATP1B1 and OATP1B3 with 13 exons identical in length. Northern blot analysis shows that Oatp1b4 is predominantly expressed in the liver. Oatp1b4 mediates sodium-independent transport of typical Organic anions including bromosulfophthalein (BSP), [D-penicillamine2,5]enkephalin (DPDPE), estradiol-17β-glucuronide (E17βG), estrone-3-sulfate and taurocholate. In addition, Oatp1b4 transports the OATP1B3-specific substrate cholecystokinin octapeptide (CCK-8). Kinetic studies showed that Oatp1b4-mediated E17βG and estrone-3-sulfate transports were monophasic with Km values of 5 ± 1 µM and 33 ± 4 µM, respectively. In conclusion, the cloned canine Oatp1b4 will provide additional molecular basis to further characterize the species difference of the OATP1B family members.

  • Role of transmembrane domain 10 for the function of Organic anion transporting Polypeptide 1B1
    Protein Science, 2009
    Co-Authors: Bruno Hagenbuch
    Abstract:

    The liver-specific Organic anion transporting Polypeptides OATP1B1 and OATP1B3 are highly homologous and share numerous substrates. However, at low concentrations OATP1B1 shows substrate selectivity for estrone-3-sulfate. In this study, we investigated the molecular mechanism for this substrate selectivity of OATP1B1 by constructing OATP1B1/1B3 chimeric transporters and by site-directed mutagenesis. Functional studies of chimeras showed that transmembrane domain 10 is critical for the function of OATP1B1. We further identified four amino acid residues, namely L545, F546, L550, and S554 in TM10, whose simultaneous mutation caused almost complete loss of OATP1B1-mediated estrone-3-sulfate transport. Comparison of the kinetics of estrone-3-sulfate transport confirmed a biphasic pattern for OATP1B1, but showed a monophasic pattern for the quadruple mutant L545S/F546L/L550T/S554T. This mutant also showed reduced transport for other OATP1B1 substrates such as bromosulfophthalein and [d-penicillamine2,5]enkephalin. Helical wheel analysis and molecular modeling suggest that L545 is facing the substrate translocation pathway, whereas F546, L550, and S554 are located inside the protein. These results indicate that L545 might contribute to OATP1B1 function by interacting with substrates, whereas F546, L550, and S554 seem important for protein structure. In conclusion, our results show that TM10 is critical for the function of OATP1B1.

Yuichi Sugiyama - One of the best experts on this subject based on the ideXlab platform.

  • whole body distribution and radiation dosimetry of 11c telmisartan as a biomarker for hepatic Organic anion transporting Polypeptide oatp 1b3
    Nuclear Medicine and Biology, 2012
    Co-Authors: Keiji Shimizu, Tadayuki Takashima, Yoshinobu Hashizume, Hiromitsu Kageyama, Tomohiko Yamane, Kazuya Maeda, Masahiro Sasaki, Yasuyoshi Watanabe, Yuichi Sugiyama, Michio Senda
    Abstract:

    Abstract Introduction Telmisartan, a nonpeptide angiotensin II AT1 receptor antagonist used as an antihypertensive drug, is specifically taken up by the liver through the OATP1B3. PET imaging with [ 11 C]telmisartan is expected to provide information about the whole body pharmacokinetics of telmisartan as well as its transport property by OATP1B3. The purpose of the study was to determine the biodistribution and radiation dosimetry of [ 11 C]telmisartan in humans. Methods Biodistribution of [ 11 C]telmisartan was measured in three rats and six healthy male human volunteers. In the rat study, a dynamic emission scan was performed for 90 min. In the human study, dynamic whole-body PET images were acquired after intravenous injection of [ 11 C]telmisartan. ROIs were defined for source organs on the PET images to measure time-course of [ 11 C]telmisartan uptake as percentage injected dose and the number of disintegration for each organ. Radiation dosimetry was calculated with OLINDA/EXM. Results In the rat study, most radioactivity was rapidly taken up by the liver and part of it was excreted into the biliary tract and intestine. Extrapolating from the rat data, the effective dose for the adult human being was estimated to be 3.65±0.01 microSv/MBq ( n =3). In the human study, most of the tracer was taken up by the liver as well, although not as rapidly as in the rat. The activity in the gall bladder and intestine increased gradually. The effective dose for the adult human being was 4.24±0.09 microSv/MBq ( n =6). Conclusions [ 11 C]Telmisartan is a safe PET tracer with a dosimetry profile comparable to other common 11 C PET tracers.

  • The Involvement of Organic Anion Transporting Polypeptide in the Hepatic Uptake of Telmisartan in Rats: PET Studies with [11C]Telmisartan
    Molecular Pharmaceutics, 2011
    Co-Authors: Tadayuki Takashima, Yoshinobu Hashizume, Machiko Murai, Yasuhiro Wada, Yumiko Katayama, Kazuya Maeda, Yuichi Sugiyama, Yasuyoshi Watanabe
    Abstract:

    Telmisartan, a selective angiotensin II receptor antagonist, is primarily excreted via hepatobiliary transport. The predominant contribution of Organic anion transporting Polypeptide (OATP) 1B3 in its hepatic uptake of telmisartan has been demonstrated by in vitro transport studies. In the present study, a quantitative positron emission tomography (PET) methodology was developed for in vivo kinetic assessment of hepatobiliary transport of telmisartan. Serial abdominal PET scans were performed in rats following intravenous administration of [11C]telmisartan as a radiotracer. PET scans revealed that [11C]telmisartan was localized primarily in the liver and some of the radioactivity moved to the intestine, which corresponds to biliary excretion. Radiometabolite analysis by radiometric HPLC showed that [11C]telmisartan was converted to its acylglucuronide, which was mainly detected in bile, but little in plasma and liver. Integration plot analysis revealed that [11C]telmisartan was taken up into the liver as ...

  • genetic polymorphisms of uptake oatp1b1 1b3 and efflux mrp2 bcrp transporters implications for inter individual differences in the pharmacokinetics and pharmacodynamics of statins and other clinically relevant drugs
    Expert Opinion on Drug Metabolism & Toxicology, 2009
    Co-Authors: Ichiro Ieiri, Shun Higuchi, Yuichi Sugiyama
    Abstract:

    Recent pharmacogenomic/pharmacogenetic studies have disclosed important roles of drug transporters in the pharmacokinetic/pharmacodynamic (PK/PD) profiles of some clinically relevant drugs. It has concurrently been explained that variations in the drug transporter genes are associated with not only inter-individual but also inter-ethnic differences in PK/PD profiles of these drugs. This review focuses on two uptake and two efflux transporters. Organic anion transporting Polypeptide (OATP) 1B1 and OATP1B3 are uptake transporters, specifically expressed in the liver, and considered important for drugs, particularly as their pharmacological target organ is the liver. Two ATP-binding cassette transporters, multi-drug resistance-associated protein 2 and breast cancer resistance protein, are efflux transporters, expressed in various human tissues, and considered particularly important for intestinal drug absorption and hepatic drug elimination. All 3-hydroxyl-3-methylglutaryl-CoA reductase inhibitors (statins) ...

  • prediction of in vivo biliary clearance from the in vitro transcellular transport of Organic anions across a double transfected madin darby canine kidney ii monolayer expressing both rat Organic anion transporting Polypeptide 4 and multidrug resistan
    Molecular Pharmacology, 2004
    Co-Authors: Makoto Sasaki, Peter J Meier, Jun Aoki, Hiroshi Suzuki, Yuichi Sugiyama
    Abstract:

    We have proposed previously that the evaluation of transcellular transport across the double-transfected Madin-Darby canine kidney II (MDCK II) monolayer that expresses both human Organic anion transporting Polypeptide 4 (OATP2/SLC21A6) and multidrug resistance associated protein 2 (MRP2/ABCC2) on the basal and apical membranes, respectively, may be useful in characterizing human biliary excretion (J Biol Chem 277: 6497-6503, 2002). However, to demonstrate that this in vitro system represents in vivo biliary excretion, it is essential to compare in vitro data with in vivo biliary excretion. The problem is that we cannot determine the human biliary excretion for many ligands. In the present study, we have established a double-transfected MDCK II monolayer that expresses both rat Oatp4/Slc21a10 and Mrp2/Abcc2 on the basal and apical membranes, respectively, for the purpose of quantitatively comparing the clearance for transcellular transport with that for in vivo biliary excretion. The basal-to-apical transport of 17beta-estradiol-17beta-d-glucuronide, pravastatin, leukotriene C(4), cyclo-[D-Asp-Pro-d-Val-Leu-d-Trp] (BQ123), temocaprilat, and taurolithocholate 3-sulfate was significantly higher than that in the opposite direction in the double transfectant. Kinetic analysis suggested that that the rate-determining step of these compounds is the uptake process. The extent of the transcellular transport across the rat double-transfectant correlated well with that across the double-transfectant for human OATP2/SLC21A6 and MRP2/ABCC2. Moreover, considering the scaling factor, the clearance values for in vitro transcellular transport correlated well with those for in vivo biliary clearance. The double-transfected MDCK II monolayer may be useful in analyzing the hepatic vectorial transport of Organic anions and in predicting in vivo biliary clearance.

  • involvement of multispecific Organic anion transporter oatp14 slc21a14 in the transport of thyroxine across the blood brain barrier
    Endocrinology, 2004
    Co-Authors: Kimio Tohyama, Hiroyuki Kusuhara, Yuichi Sugiyama
    Abstract:

    The present study was aimed at investigating the involvement of mouse Organic anion transporting Polypeptide 14 (mOatp14) in the uptake of T4 across the blood-brain barrier. Functional expression of mOatp14 in HEK293 cells revealed that T4 and rT3 are high affinity substrates of mOatp14 (Michaelis constant, 0.34 and 0.46 μm, respectively), and the specific uptake of T3 was 4-fold less than that of T4 and rT3. Taurocholate, probenecid, and estrone-3-sulfate were moderate inhibitors for mOatp14, whereas digoxin (substrate of Oatp2), benzylpenicillin (substrate of Oat3), and large neutral amino acids had no effect. mOatp14 is widely expressed throughout the brain, except for the cerebellum. The expression of mOatp14 in the isolated brain capillaries and the choroid plexus was shown by Western blot. The uptake clearance of T4 by the cerebral cortex determined using the in situ brain perfusion technique in mice was 580 μl/min·g tissue, 3-fold greater than that by the cerebellum, and a saturable component (Mich...

Peter J Meier - One of the best experts on this subject based on the ideXlab platform.

  • Characterization of two splice variants of human Organic anion transporting Polypeptide 3A1 isolated from human brain
    American Journal of Physiology-cell Physiology, 2006
    Co-Authors: Robert Huber, Bruno Hagenbuch, Peter J Meier, Marguerite-anne Sidler Pfändler, Wenting Zhang-fu, Simone Leuthold, Gerd Folkers, Bruno Stieger
    Abstract:

    In the present study we isolated two splice variants of Organic anion transporting Polypeptide 3A1 (OATP3A1_v1 and OATP3A1_v2) from human brain. OATP3A1_v2 lacks 18 amino acids (aa) at the COOH-ter...

  • Application of QSAR analysis to Organic anion transporting Polypeptide 1a5 (Oatp1a5) substrates
    Bioorganic & Medicinal Chemistry, 2005
    Co-Authors: Mine Yarim, Bruno Hagenbuch, Peter J Meier, Robert Huber, Stefano Moro, Chosei Kaseda, Toru Kashima, Gerd Folkers
    Abstract:

    Organic anion transporting Polypeptide 1a5, Slco1a5 (previously called Oatp3, Slc21a7) is a multispecific transmembrane transport protein that belongs to the OATP/SLCO superfamily of solute carriers. It is expressed in several epithelial barriers such as the small intestine and the choroid plexus where it might play an important role in the disposition of numerous endogenous and exogenous Organic compounds. Since the molecular basis of the multispecificity of Oatp1a5 is not known and the three-dimensional structure not solved yet, we used three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques to obtain topological information on the substrate binding site of the protein. We aligned a heterogeneous data set of 18 Oatp1a5 substrates using the Genetic Algorithm Similarity Program (GASP) and performed comparative molecular field analysis (CoMFA) using this alignment. This resulted in a reasonable QSAR model including steric and electrostatic fields with a leave-one-out cross-validated r(cv)2 value of 0.705 and a no-cross-validated regression coefficient r2 value of 0.949. Based on the derived model we identified new potential Oatp1a5 substrates and confirmed their predicted apparent affinity values experimentally.

  • prediction of in vivo biliary clearance from the in vitro transcellular transport of Organic anions across a double transfected madin darby canine kidney ii monolayer expressing both rat Organic anion transporting Polypeptide 4 and multidrug resistan
    Molecular Pharmacology, 2004
    Co-Authors: Makoto Sasaki, Peter J Meier, Jun Aoki, Hiroshi Suzuki, Yuichi Sugiyama
    Abstract:

    We have proposed previously that the evaluation of transcellular transport across the double-transfected Madin-Darby canine kidney II (MDCK II) monolayer that expresses both human Organic anion transporting Polypeptide 4 (OATP2/SLC21A6) and multidrug resistance associated protein 2 (MRP2/ABCC2) on the basal and apical membranes, respectively, may be useful in characterizing human biliary excretion (J Biol Chem 277: 6497-6503, 2002). However, to demonstrate that this in vitro system represents in vivo biliary excretion, it is essential to compare in vitro data with in vivo biliary excretion. The problem is that we cannot determine the human biliary excretion for many ligands. In the present study, we have established a double-transfected MDCK II monolayer that expresses both rat Oatp4/Slc21a10 and Mrp2/Abcc2 on the basal and apical membranes, respectively, for the purpose of quantitatively comparing the clearance for transcellular transport with that for in vivo biliary excretion. The basal-to-apical transport of 17beta-estradiol-17beta-d-glucuronide, pravastatin, leukotriene C(4), cyclo-[D-Asp-Pro-d-Val-Leu-d-Trp] (BQ123), temocaprilat, and taurolithocholate 3-sulfate was significantly higher than that in the opposite direction in the double transfectant. Kinetic analysis suggested that that the rate-determining step of these compounds is the uptake process. The extent of the transcellular transport across the rat double-transfectant correlated well with that across the double-transfectant for human OATP2/SLC21A6 and MRP2/ABCC2. Moreover, considering the scaling factor, the clearance values for in vitro transcellular transport correlated well with those for in vivo biliary clearance. The double-transfected MDCK II monolayer may be useful in analyzing the hepatic vectorial transport of Organic anions and in predicting in vivo biliary clearance.

  • identification of a novel human Organic anion transporting Polypeptide as a high affinity thyroxine transporter
    Molecular Endocrinology, 2002
    Co-Authors: F Pizzagalli, Bruno Hagenbuch, Bruno Stieger, Gerd Folkers, U Klenk, Peter J Meier
    Abstract:

    Transport of various amphipathic Organic compounds is mediated by Organic anion transporting Polypeptides (OATPs in humans, Oatps in rodents), which belong to the solute carrier family 21A (SLC21A/Slc21a). Several of these transporters exhibit a broad and overlapping substrate specificity and are expressed in a variety of different tissues. We have isolated and functionally characterized OATP-F (SLC21A14), a novel member of the OATP family. The cDNA (3059 bp) contains an open reading frame of 2136 bp encoding a protein of 712 amino acids. Its gene containing 15 exons is located on chromosome 12p12. OATP-F exhibits 47–48% amino acid identity with OATP-A, OATP-C, and OATP8, the genes of which are clustered on chromosome 12p12. OATP-F is predominantly expressed in multiple brain regions and Leydig cells of the testis. OATP-F mediates high affinity transport of T4 and reverse T3 with apparent Km values of approximately 90 nm and 128 nm, respectively. Substrates less well transported by OATP-F include T3, brom...

  • Functional characterization of the mouse Organic-Anion-Transporting Polypeptide 2.
    Biochimica et Biophysica Acta, 2002
    Co-Authors: Jessica E. Van Montfoort, Peter J Meier, Thomas E. Schmid, Ilse-dore Adler, Bruno Hagenbuch
    Abstract:

    We have isolated and functionally characterized an additional murine member of the Organic-Anion-Transporting Polypeptide (Oatp) family of membrane transport proteins from mouse liver. The 3.6 kb cDNA insert contains an open reading frame of 2010 bp coding for a 670 amino acid protein. Based on its amino acid identity of 88% to the rat Oatp2, it is considered the mouse Oatp2 orthologue. Functional expression in Xenopus laevis oocytes demonstrated that mouse Oatp2 transports several general Oatp substrates such as estrone-3-sulfate, dehydroepiandrosterone sulfate (DHEAS), ouabain and BQ-123 but hardly any taurocholate nor rocuronium or deltorphin II. The high-affinity rat Oatp2 substrate digoxin is transported with a rather low affinity with an apparent K(m) value of 5.7 microM. Bromosulfophthalein (BSP), a substrate not transported by the rat Oatp2, is transported very well by mouse Oatp2. Northern blot analysis demonstrated a predominant expression in the liver with additional signals in kidney and brain. Using fluorescence in situ hybridization, the Oatp2 gene (gene symbol Slc21a5) was mapped to chromosome 6G1-G3.

Ikumi Tamai - One of the best experts on this subject based on the ideXlab platform.

  • Roles of Organic Anion Transporting Polypeptide 2A1 (OATP2A1/SLCO2A1) in Regulating the Pathophysiological Actions of Prostaglandins
    The AAPS Journal, 2017
    Co-Authors: Takeo Nakanishi, Ikumi Tamai
    Abstract:

    Solute carrier Organic anion transporter family member 2A1 (OATP2A1, encoded by the SLCO2A1 gene), which was initially identified as prostaglandin transporter (PGT), is expressed ubiquitously in tissues and mediates the distribution of prostanoids, such as PGE_2, PGF_2α, PGD_2 and TxB_2. It is well known to play a key role in the metabolic clearance of prostaglandins, which are taken up into the cell by OATP2A1 and then oxidatively inactivated by 15-ketoprostaglandin dehydrogenase (encoded by HPGD ); indeed, OATP2A1-mediated uptake is the rate-limiting step of PGE_2 catabolism. Consequently, since OATP2A1 activity is required for termination of prostaglandin signaling via prostanoid receptors, its inhibition can enhance such signaling. On the other hand, OATP2A1 can also function as an Organic anion exchanger, mediating efflux of prostaglandins in exchange for import of anions such as lactate, and in this context, it plays a role in the release of newly synthesized prostaglandins from cells. These different functions likely operate in different compartments within the cell. OATP2A1 is reported to function at cytoplasmic vesicle/organelle membranes. As a regulator of the levels of physiologically active prostaglandins, OATP2A1 is implicated in diverse physiological and pathophysiological processes in many organs. Recently, whole exome analysis has revealed that recessive mutations in SLCO2A1 cause refractory diseases in humans, including primary hypertrophic osteoarthropathy (PHO) and chronic non-specific ulcers in small intestine (CNSU). Here, we review and summarize recent information on the molecular functions of OATP2A1 and on its physiological and pathological significance.

  • Organic Anion Transporting Polypeptide (OATP)2B1 Contributes to Gastrointestinal Toxicity of Anticancer Drug SN-38, Active Metabolite of Irinotecan Hydrochloride.
    Drug Metabolism and Disposition, 2015
    Co-Authors: Daichi Fujita, Yoshimasa Saito, Takeo Nakanishi, Ikumi Tamai
    Abstract:

    Gastrointestinal toxicity, such as late-onset diarrhea, is a significant concern in irinotecan hydrochloride (CPT-11)–containing regimens. Prophylaxis of late-onset diarrhea has been reported with use of Japanese traditional ( Kampo ) medicine containing baicalin and with the antibiotic cefixime, and this has been explained in terms of inhibition of bacterial deconjugation of SN-38-glucuronide since unconjugated SN-38 (active metabolite of CPT-11) is responsible for the gastrointestinal toxicity. It is also prerequisite for SN-38 to be accumulated in intestinal tissues to exert toxicity. Based on the fact that liver-specific Organic anion transporting Polypeptide (OATP)1B1, a member of the same family as OATP2B1, is known to be involved in hepatic transport of SN-38, we hypothesized that intestinal transporter OATP2B1 contributes to the accumulation of SN-38 in gastrointestinal tissues, and its inhibition would help prevent associated toxicity. We found that uptake of SN-38 by OATP2B1-expressing Xenopus oocytes was significantly higher than that by control oocytes. OATP2B1-mediated uptake of SN-38 was saturable, pH dependent, and decreased in the presence of baicalin, cefixime, or fruit juices such as apple juice. In vivo gastrointestinal toxicity of SN-38 in mice caused by oral administration for consecutive 5 days was prevented by coingestion of apple juice. Thus, OATP2B1 contributes to the uptake of SN-38 by intestinal tissues, triggering gastrointestinal toxicity. So, in addition to the reported inhibition of bacterial β -glucuronidase by cefixime or baicalin, inhibition of OATP2B1 may also contribute to prevention of gastrointestinal toxicity. Apple juice may be helpful for prophylaxis of late-onset diarrhea observed in CPT-11 therapy without disturbance of the intestinal microflora.

  • Intestinal absorption of HMG-CoA reductase inhibitor pitavastatin mediated by Organic anion transporting Polypeptide and P-glycoprotein/multidrug resistance 1.
    Drug Metabolism and Pharmacokinetics, 2010
    Co-Authors: Yoshiyuki Shirasaka, Megumi Shichiri, Takeo Nakanishi, Kensuke Suzuki, Ikumi Tamai
    Abstract:

    Summary: The purpose of this study was to investigate the involvement of Organic anion transporting Polypeptide (OATP/Oatp) and P-glycoprotein (P-gp)/multidrug resistance 1 (MDR1/Mdr1) in intestinal absorption of pitavastatin. Pitavastatin was found to be a substrate for human OATP1A2, OATP2B1, and MDR1 and rat Oatp1a5, Oatp2b1, and Mdr1a in experiments using transporter-expressing Xenopus oocytes and LLC-PK1 cell systems. Naringin inhibited Oatp1a5- and Mdr1a-mediated transport of pitavastatin with IC 50 values of 18.5 and 541 μM, respectively. The difference in the IC 50 values of naringin for Oatp1a5 and Mdr1a-mediated pitavastatin transport may account for the complex concentrationdependent effect of naringin on the intestinal absorption of pitavastatin. Rat intestinal permeability of pitavastatin measured by the in situ closed-loop perfusion method was indeed significantly reduced by 200 μM naringin, but was significantly increased by 1000 μM naringin. Furthermore, the permeability was significantly increased by elacridar, a potent inhibitor of Mdr1, while the permeability was significantly decreased in the presence of both elacridar and naringin, suggesting that Oatp1a5 and Mdr1a are both involved in intestinal absorption of pitavastatin. Our present results indicate that OATP/Oatp and MDR1/ Mdr1 play roles in the intestinal absorption of pitavastatin as influx and efflux transporters, respectively.

  • Intestinal Absorption of HMG-CoA Reductase Inhibitor Pravastatin Mediated by Organic Anion Transporting Polypeptide
    Pharmaceutical Research, 2010
    Co-Authors: Yoshiyuki Shirasaka, Takeo Nakanishi, Kensuke Suzuki, Ikumi Tamai
    Abstract:

    Purpose The purpose of this study is to clarify the impact of Organic anion transporting Polypeptide (Oatp) on intestinal absorption of the HMG-CoA reductase inhibitor, pravastatin. Methods OATP/Oatp-mediated pravastatin uptake was evaluated with Xenopus oocytes systems. Intestinal permeability was measured by an in situ closed loop method in rats. In vivo pravastatin absorption was kinetically assessed by measuring plasma concentration after oral administration in rats. Results Uptake of pravastatin by Oatp1a5, Oatp2b1, OATP1A2, and OATP2B1 cRNA-injected Xenopus oocytes was significantly increased compared with that by water-injected oocytes. Naringin, a potent inhibitor of Oatps and Mdr1, decreased the Oatp1a5-mediated uptake of pravastatin with IC _50 value of 30.4 μM. Rat intestinal permeability of pravastatin was significantly reduced in the presence of 1,000 μM naringin. Similar results were obtained in in vivo absorption studies in rats. Furthermore, no significant change in the permeability was observed in the presence of elacridar, a potent inhibitor of both Mdr1 and Bcrp, though the permeability was significantly decreased in the presence of both elacridar and naringin, suggesting that Mdr1 and Bcrp are not involved in intestinal absorption of pravastatin. Conclusion Oatp, but not by Mdr1 or Bcrp, contributes to the intestinal absorption of pravastatin in rats.

  • Intestinal Absorption of HMG-CoA Reductase Inhibitor Pravastatin Mediated by Organic Anion Transporting Polypeptide
    Pharmaceutical Research, 2010
    Co-Authors: Yoshiyuki Shirasaka, Takeo Nakanishi, Kensuke Suzuki, Ikumi Tamai
    Abstract:

    Purpose The purpose of this study is to clarify the impact of Organic anion transporting Polypeptide (Oatp) on intestinal absorption of the HMG-CoA reductase inhibitor, pravastatin.

Ken Iseki - One of the best experts on this subject based on the ideXlab platform.

  • Black tea extract and theaflavin derivatives affect the pharmacokinetics of rosuvastatin by modulating Organic anion transporting Polypeptide (OATP) 2B1 activity.
    Biopharmaceutics & Drug Disposition, 2019
    Co-Authors: Ayuko Kondo, Katsuya Narumi, Ayako Furugen, Masaki Kobayashi, Keisuke Okuhara, Yuka Takahashi, Ken Iseki
    Abstract:

    Theaflavins (TFs) are derived from black tea, an important source of dietary polyphenols. Although the potential interactions between dietary polyphenols and drugs have been demonstrated through in vitro and in vivo studies, little information is available concerning the influence of TFs on drug disposition. Organic anion transporting Polypeptide 2B1 (OATP2B1) is expressed in human enterocytes and plays a role in the intestinal absorption of numerous drugs. The current study evaluated the effects of black tea extracts on the pharmacokinetics of rosuvastatin in rats, and investigated the effect of four major TFs (theaflavin, theaflavin-3-gallate, theaflavin-3'-gallate and theaflavin-3,3'-digallate) on the transport activity of OATP2B1. Black tea extracts significantly decreased the maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC0 -8 ) of rosuvastatin by 48% and 37%, respectively (p 

  • black tea extract and theaflavin derivatives affect the pharmacokinetics of rosuvastatin by modulating Organic anion transporting Polypeptide oatp 2b1 activity
    Biopharmaceutics & Drug Disposition, 2019
    Co-Authors: Ayuko Kondo, Katsuya Narumi, Ayako Furugen, Masaki Kobayashi, Keisuke Okuhara, Yuka Takahashi, Ken Iseki
    Abstract:

    : Theaflavins (TFs) are derived from black tea, an important source of dietary polyphenols. Although the potential interactions between dietary polyphenols and drugs have been demonstrated through in vitro and in vivo studies, little information is available concerning the influence of TFs on drug disposition. Organic anion transporting Polypeptide 2B1 (OATP2B1) is expressed in human enterocytes and plays a role in the intestinal absorption of numerous drugs. The current study evaluated the effects of black tea extracts on the pharmacokinetics of rosuvastatin in rats, and investigated the effect of four major TFs (theaflavin, theaflavin-3-gallate, theaflavin-3'-gallate and theaflavin-3,3'-digallate) on the transport activity of OATP2B1. Black tea extracts significantly decreased the maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC0 -8 ) of rosuvastatin by 48% and 37%, respectively (p < 0.001 and p < 0.01, respectively). Moreover, OATP2B1-mediated rosuvastatin and estrone-3-sulfate uptake was significantly reduced in the presence of TFs. A kinetic study revealed that the uptake efficiency (in terms of Vmax /Km ) of rosuvastatin was decreased following treatment with TFs. Black tea extracts also reduced OATP2B1-mediated rosuvastatin uptake. These results suggest that black tea reduces the plasma concentrations of rosuvastatin by inhibiting the intestinal OATP2B1-mediated transport of rosuvastatin.

  • Organic Anion-Transporting Polypeptide (OATP) 2B1 contributes to the cellular uptake of theaflavin
    Drug Metabolism and Pharmacokinetics, 2016
    Co-Authors: Ayuko Kondo, Katsuya Narumi, Jiro Ogura, Ai Sasaki, Keisuke Yabe, Taku Kobayashi, Ayako Furugen, Masaki Kobayashi, Ken Iseki
    Abstract:

    Abstract Organic Anion-Transporting Polypeptide (OATP) 2B1 has been reported in the apical membranes of the human small intestinal epithelium, where it contributes to the intestinal absorption of pharmacologically active drugs. To investigate the potential for OATP2B1-mediated drug–food interactions, the effects of several polyphenolic compounds on OATP2B1-mediated estrone-3-sulfate (E3S) transport were studied by using OATP2B1-expressing HEK293 cells. Our results showed that some compounds, especially theaflavin, were strong inhibitors of OATP2B1-mediated E3S uptake. Theaflavin showed a significantly higher uptake into the OATP2B1-expressing HEK293 cells than the control cells. The concentration dependence of the uptake of theaflavin was determined over a range of concentrations (0.5–100 μM) and the kinetic parameters (Km and Vmax) of theaflavin uptake were found to be 5.12 ± 0.67 μM and 41.6 ± 1.3 pmol/mg protein/min, respectively. The OATP2B1-mediated theaflavin uptake was inhibited by known OATP2B1 substrates such as E3S, bromsulphthalein (BSP), dehydroepiandrosterone-3-sulfate (DHEAS), and fluvastatin. Our results indicate that theaflavin is a novel substrate of OATP2B1. The results of this study might be helpful to predict the potential OATP2B1-mediated drug–theaflavin interactions and to avoid undesirable clinical consequences.

  • Contribution of Organic anion transporting Polypeptide OATP2B1 to amiodarone accumulation in lung epithelial cells
    Biochimica et Biophysica Acta, 2009
    Co-Authors: Satoru Seki, Masaki Kobayashi, Shirou Itagaki, Takeshi Hirano, Ken Iseki
    Abstract:

    Abstract The accumulation mechanisms of amiodarone (AMD) involving transporters in lung alveolar epithelial type II cells were studied. The uptake of AMD was examined using human alveolar epithelial-derived cell line A549 as a model. AMD was transported by the carrier-mediated system, and the apparent K m and V max values were 66.8 ± 30.3 μM and 49.7 ± 9.7 nmol/mg protein/5 min, respectively. The uptake of AMD by A549 cells was Na + -independent and was inhibited by substrates of human Organic anion transporting Polypeptide (OATP). The inhibition profiles were similar to the inhibitory effects of several compounds on OATP2B1-mediated E-3-S transport, and RT-PCR analysis showed mRNA expression of OATP2B1 and 1B3 in A549 cells. SiRNAs targeted to the OATP2B1 gene decreased the OATP2B1 mRNA expression level in A549 cells up to about 50% and reduced the uptake of AMD up to about 40%. These results indicate that AMD uptake mediated by carriers, including OATP2B1, might lead to accumulation of AMD in the lung and AMD-induced pulmonary toxicity (AIPT).