Small-Dosing Clinical Study: Pharmacokinetic, Pharmacogenomic (SLCO2B1 and ABCG2), and Interaction (Atorvastatin and Grapefruit Juice) Profiles of 5 Probes for OATP2B1 and BCRP

• Published in: Journal of pharmaceutical sciences 2017-09, Vol.106 (9), p.2688-2694
• Main Authors: Kashihara, Yushi, Ieiri, Ichiro, Yoshikado, Takashi, Maeda, Kazuya, Fukae, Masato, Kimura, Miyuki, Hirota, Takeshi, Matsuki, Shunji, Irie, Shin, Izumi, Noritomo, Kusuhara, Hiroyuki, Sugiyama, Yuichi
• Format: Article
• Language: English
• Subjects: ABC transporters; Adult; Atorvastatin Calcium - chemistry; Atorvastatin Calcium - metabolism; Atorvastatin Calcium - pharmacokinetics; ATP Binding Cassette Transporter, Sub-Family B - metabolism; ATP Binding Cassette Transporter, Sub-Family G, Member 2 - metabolism; Celiprolol - chemistry; Celiprolol - pharmacokinetics; Citrus paradisi - metabolism; Dose-Response Relationship, Drug; Drug Interactions; Female; Food-Drug Interactions; Genotype; Glyburide - chemistry; Glyburide - pharmacokinetics; Humans; Intestinal Absorption; Male; Neoplasm Proteins - metabolism; Organic Anion Transporters - metabolism; organic anion-transporting polypeptide transporters; Pharmacogenetics - methods; pharmacogenomics; pharmacokinetics; Rosuvastatin Calcium - chemistry; Rosuvastatin Calcium - pharmacokinetics; Sulfasalazine - chemistry; Sulfasalazine - pharmacokinetics; Sumatriptan - chemistry; Sumatriptan - pharmacokinetics
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2017.03.010

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.