Effect of OATP1B1 genotypes on plasma concentrations of endogenous OATP1B1 substrates and drugs,and their association in healthy volunteers |
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| Affiliation: | 1. Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan;2. Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, 812-8582, Japan;3. Sugiyama Lab, RIKEN Innovation Center, RIKEN, Yokohama, Japan;4. Fukuoka Mirai Hospital Clinical Research Center, Fukuoka, 813-0017, Japan;1. Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki, Japan;2. Chromosome Engineering Research Center, Tottori University, Tottori, Japan;3. Quality and Reliability Assurance Division, Taiho Pharmaceutical Co. Ltd., Tokushima, Japan;4. Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan;5. Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Tottori, Japan;1. Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan;2. Division of Cancer Genome and Pharmacotherapy, Department of Clinical Pharmacy, Showa University School of Pharmacy, Tokyo, Japan;1. Clinical Pharmacology, Clinical Research, Pfizer Global R&D, Tokyo Laboratories, Pfizer Japan Inc., Tokyo, Japan;2. Department of Drug Development Science & Clinical Evaluation, Keio University of Pharmacy, Tokyo, Japan;3. Clinical Pharmacology, Pfizer Inc, New York, NY, USA;4. Laboratory of Clinical Pharmacology, Yokohama University of Pharmacy, Kanagawa, Japan;1. Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea;2. Department of Obstetrics and Gynecology, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea;3. Department of Obstetrics and Gynecology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea;4. Kidney Research Institute, Seoul National University Medical Research Center, Seoul, Republic of Korea;1. Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73117;2. Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield S2 4SU, UK;3. Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73126;1. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan;3. RIKEN Center for Life Science Technologies and Center for Biosystems Dynamics Research, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047 Japan;4. Sugiyama Laboratory, RIKEN Baton Zone Program, RIKEN Cluster for Science, Technology and Innovation Hub, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan |
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| Abstract: | This study aimed to elucidate the impact of OATP1B1 genotype (*1b/*1b, *1b/*15, and *15/*15) on plasma concentrations of endogenous OATP1B1 substrates. Healthy volunteers with OATP1B1 *1b/*1b (n = 10), *1b/*15 (n = 7), or *15/*15 (n = 2) received oral administration of a cocktail of statins (atorvastatin, pitavastatin, rosuvastatin, and fluvastatin). Mean area under the plasma concentration of atorvastatin, pitavastatin, and rosuvastatin in OATP1B1 *15/*15 were 2.2, 1.7 and 1.58-times greater than the corresponding values in OATP1B1 *1b/*1b, respectively, whereas that of fluvastatin was identical to those in other OATP1B1 genotypes. OATP1B1 *15/*15 also showed higher mean plasma concentrations of OATP1B1 endogenous substrates compared with the other OATP1B1 genotypes, such as coproporphyrin I, glycochenodeoxycholate sulfate (GCDCA-S), lithocholate sulfate (LCA-S), glycolithocholate sulfate (GLCA-S) and taurolithocholate sulfate (TLCA-S), but not total or direct bilirubin, chenodeoxycholate-24-glucuronide, or ω-dicarboxylic long-chain fatty acids. Area under the plasma concentration-time curves of plasma coproporphyrin I and GLCA-S discriminated OATP1B1 genotype *15/*15 from the other genotypes. In combination with previously published clinical studies, these results support the notion that coproporphyrin I, and GLCA-S and GCDCA-S could be a surrogate probe for assessing human in vivo OATP1B1 activities. |
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| Keywords: | OATP1B1 genotype Statin Endogenous substrate Biomarker Coproporphyrin I Gender difference AUC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0045" }," $$" :[{" #name" :" text" ," _" :" area under the plasma concentration-time curve CP-I" },{" #name" :" keyword" ," $" :{" id" :" kwrd0055" }," $$" :[{" #name" :" text" ," _" :" coproporphyrin I CDCA-24G" },{" #name" :" keyword" ," $" :{" id" :" kwrd0065" }," $$" :[{" #name" :" text" ," _" :" chenodeoxycholate-24-glucuronide CV" },{" #name" :" keyword" ," $" :{" id" :" kwrd0075" }," $$" :[{" #name" :" text" ," _" :" coefficient of variation DDI" },{" #name" :" keyword" ," $" :{" id" :" kwrd0085" }," $$" :[{" #name" :" text" ," _" :" drug–drug interaction GCDCA-S" },{" #name" :" keyword" ," $" :{" id" :" kwrd0095" }," $$" :[{" #name" :" text" ," _" :" glycochenodeoxycholate-3-sulfate GLCA-S" },{" #name" :" keyword" ," $" :{" id" :" kwrd0105" }," $$" :[{" #name" :" text" ," _" :" glycolithocholate sulfate LC–MS/MS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0115" }," $$" :[{" #name" :" text" ," _" :" liquid chromatography-tandem mass spectrometry LCA-S" },{" #name" :" keyword" ," $" :{" id" :" kwrd0125" }," $$" :[{" #name" :" text" ," _" :" lithocholate sulfate MATE1" },{" #name" :" keyword" ," $" :{" id" :" kwrd0135" }," $$" :[{" #name" :" text" ," _" :" multidrug and toxin extrusion protein 1 MRM" },{" #name" :" keyword" ," $" :{" id" :" kwrd0145" }," $$" :[{" #name" :" text" ," _" :" multiple-reaction monitoring OATP1B1" },{" #name" :" keyword" ," $" :{" id" :" kwrd0155" }," $$" :[{" #name" :" text" ," _" :" organic anion-transporting polypeptide 1B1 OATP1B3" },{" #name" :" keyword" ," $" :{" id" :" kwrd0165" }," $$" :[{" #name" :" text" ," _" :" organic anion-transporting polypeptide 1B3 OCT2" },{" #name" :" keyword" ," $" :{" id" :" kwrd0175" }," $$" :[{" #name" :" text" ," _" :" organic cation transporter 2 TLCA-S" },{" #name" :" keyword" ," $" :{" id" :" kwrd0185" }," $$" :[{" #name" :" text" ," _" :" taurolithocholate sulfate |
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