Small-Dosing Clinical Study: Pharmacokinetic, Pharmacogenomic (SLCO2B1 and ABCG2), and Interaction (Atorvastatin and Grapefruit Juice) Profiles of 5 Probes for OATP2B1 and BCRP.
The aims of this study were (1) to investigate the effects of atorvastatin (10 mg, therapeutic dose) and grapefruit juice (GFJ), inhibitors of OATP2B1, on the pharmacokinetics of substrates for OATP2B1 and BCRP under oral small-dosing conditions (300 μg sulfasalazine, 250 μg rosuvastatin, 300 μg glibenclamide, 1200 μg celiprolol, and 600 μg sumatriptan), and (2) to evaluate the contribution of SLCO2B1*3 and ABCG2 c.421C>A polymorphisms to the pharmacokinetics of the 5 test drugs in 23 healthy volunteers. In the 3 phases, the test drugs were administered to volunteers with either water (control phase), atorvastatin, or GFJ. GFJ but not atorvastatin reduced the exposure of the test drugs significantly more than the control phase, suggesting that all 5 test drugs are substrates for OATP2B1. The SLCO2B1*3 genotype had no effect on the pharmacokinetics of the test drugs. In contrast, the exposure of sulfasalazine and rosuvastatin was significantly higher in ABCG2 421C/A than in ABCG2 421C/C individuals at all 3 phases, even under small-dosing conditions.
Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 8128582, Japan.
Yushi
Y
Kashihara
Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 8128582, Japan. Electronic address: ieiri-ttr@umin.ac.jp.
Ichiro
I
Ieiri
Sugiyama Laboratory, RIKEN Innovation Center, Yokohama 2300045, Japan.
Takashi
T
Yoshikado
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 1130033, Japan.
Kazuya
K
Maeda
Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 8128582, Japan.
Masato
M
Fukae
Kyushu Pharmacology Research Clinic (current name is Fukuoka Mirai Hospital Clinical Research Center), Fukuoka 8130017, Japan.
Miyuki
M
Kimura
Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 8128582, Japan.
Takeshi
T
Hirota
Kyushu Pharmacology Research Clinic (current name is Fukuoka Mirai Hospital Clinical Research Center), Fukuoka 8130017, Japan.
Shunji
S
Matsuki
Kyushu Pharmacology Research Clinic (current name is Fukuoka Mirai Hospital Clinical Research Center), Fukuoka 8130017, Japan.
Shin
S
Irie
Kyushu Pharmacology Research Clinic (current name is Fukuoka Mirai Hospital Clinical Research Center), Fukuoka 8130017, Japan.
Noritomo
N
Izumi
Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 1130033, Japan.
Hiroyuki
H
Kusuhara
Sugiyama Laboratory, RIKEN Innovation Center, Yokohama 2300045, Japan.
Yuichi
Y
Sugiyama
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism*; D000328:Adult; D000069059:Atorvastatin / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D017272:Celiprolol / Q000737:chemistry / Q000493:pharmacokinetics; D032083:Citrus paradisi / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D018565:Food-Drug Interactions; D005838:Genotype; D005905:Glyburide / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*; D010597:Pharmacogenetics / Q000379:methods*; D000068718:Rosuvastatin Calcium / Q000737:chemistry / Q000493:pharmacokinetics; D012460:Sulfasalazine / Q000737:chemistry / Q000493:pharmacokinetics; D018170:Sumatriptan / Q000737:chemistry / Q000493:pharmacokinetics
C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; C450859:SLCO2B1 protein, human; D012460:Sulfasalazine; D000068718:Rosuvastatin Calcium; D018170:Sumatriptan; D000069059:Atorvastatin; D017272:Celiprolol; D005905:Glyburide
ABC transporters; drug interactions; intestinal absorption; organic anion-transporting polypeptide transporters; pharmacogenomics; pharmacokinetics