Comparative analysis of the single-molecule transport kinetics of OATP1B1 genetic variants

被引：0

作者：

Tsujii, Kazunari ^{[1
]}

Yajima, Kodai ^{[1
]}

Akiyoshi, Takeshi ^{[1
,2
]}

Sakamoto, Kazuho ^{[7
]}

Suzuki, Yoshiaki ^{[4
]}

Oka, Takayuki ^{[5
]}

Imaoka, Ayuko ^{[1
]}

Yamamura, Hisao ^{[4
]}

Kurokawa, Junko ^{[3
]}

Ohtani, Hisakazu ^{[1
,2
,6
]}

机构：

[1] Keio Univ, Grad Sch Pharmaceut Sci, Div Clin Pharm, 1-5-30 Shibakoen, Minato Ku, Tokyo 1058512, Japan

[2] Keio Univ, Sch Med, Dept Clin Pharm, 35 Shinanomachi, Shinjuku Ku, Tokyo 1608582, Japan

[3] Univ Shizuoka, Sch Pharmaceut Sci, Dept Bioinformat Pharmacol, 52-1 Yada, Suruga Ku, Shizuoka, Shizuoka 4228526, Japan

[4] Nagoya City Univ, Grad Sch Pharmaceut Sci, Dept Mol & Cellular Pharmacol, 3-1 Tanabedori, Mizuho Ku, Nagoya 4678603, Japan

[5] Tokyo Lab, Nan Technol Japan KK, Wakamatsu Cho, Shinjuku Ku, Tokyo 1620056, Japan

[6] Keio Univ Hosp, Dept Pharm, 35 Shinanomachi, Shinjuku Ku, Tokyo 1608582, Japan

[7] Int Univ Hlth & Welf, Sch Pharm, 2600-1 Kitakanemaru, Otawara, Tochigi 3248501, Japan

来源：

JOURNAL OF PHARMACOLOGICAL SCIENCES | 2025年 / 158卷 / 03期

关键词：

Transporter; Intrinsic activity; Patch clamp; BK channel; POLYMORPHISMS; VARIABILITY; EXPRESSION; DRUG; DISPOSITION; PRAVASTATIN;

D O I：

10.1016/j.jphs.2025.04.005

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Several genetic variants of OATP1B1, a hepatic uptake transporter, increase the blood concentrations of substrate drugs, e.g., *15 carriers exhibit higher blood substrate concentrations than *1b carriers. It remains unclear whether these differences are due to changes in expression or intrinsic activity (transport activity per OATP1B1 molecule). This study compared the intrinsic activity of four OATP1B1 variants, *1a, *1b, *5, and *15, using HEK293 cell lines that co-expressed large-conductance Ca2+-activated K+ (BK) channels and one of the OATP1B1 variants. To estimate the kinetic parameters Km and Vmax, 2 ', 7 '-dichlorofluorescein uptake was evaluated. The number of OATP molecules per cell (QT) was calculated from BK channel-mediated whole-cell conductance and the OATP1B1/BK channel expression ratio (rho) (determined by LC-MS/MS). Vmax,int (maximum intrinsic transport velocity) was obtained by dividing Vmax by QT, and intrinsic clearance (CLint) was calculated as Vmax,int/Km. The Km values of *1a, *1b, *5, and *15 were 12.5, 9.19, 7.53, and 10.4 mu M, and their Vmax,int values were 3.0, 7.0, 1.5, and 1.2 x 10-21 mol/OATP molecule/min, respectively. Accordingly, the CLintvalue for OATP1B1*15 was 15 % lower than that for OATP1B1*1b, suggesting that the increased blood substrate concentrations observed in OATP1B1*15 carriers may be due to the decreased intrinsic activity of OATP1B1*15.

引用

页码：166 / 171

页数：6

共 32 条

[1] CELLULAR FRACTIONATION AND ISOLATION OF THE PLASMA-MEMBRANE OF BURKITTS-LYMPHOMA CELLS [J].