Contribution of OATP1B1 and OATP1B3 to Hepatic Uptake of SC-62807 in Humans
| Reference compounds | SC-62807 | |||||
| Lot no. and transporter | (1) Human hepatocytes* (CLhepatocyte,ref [μL/min/106 cells]) | (2) OATP1B1-HEK or OATP1B3-HEK (CL1B1,ref or CL1B3,ref [μL/min/mg protein]) | (3) R1B1 and R1B3: (1)/(2) (CLhepatocyte,ref/CL1B1,ref or CLhepatocyte,ref/CL1B3,ref) | (4) OATP1B1-HEK or OATP1B3-HEK (CL1B1,SC or CL1B3,SC [μL/min/mg protein]) | Human hepatocytes (3) × (4) (CLhepatocyte,SC [μL/min/106 cells]) | Contribution (%) |
| OCF | ||||||
| OATP1B1 | 110 | 311 ± 25.8 | 0.353 | 10.2 | 3.60 | 30.2 |
| OATP1B3 | 7.89 | 47.0 ± 5.48 | 0.168 | 49.4 | 8.30 | 69.8 |
| 094 | ||||||
| OATP1B1 | 134 | 311 ± 25.8 | 0.430 | 10.2 | 4.38 | 54.3 |
| OATP1B3 | 3.50 | 47.0 ± 5.48 | 0.0745 | 49.4 | 3.68 | 45.7 |
| ETR | ||||||
| OATP1B1 | 57.7 | 311 ± 25.8 | 0.185 | 10.2 | 1.89 | 47.0 |
| OATP1B3 | 2.02 | 47.0 ± 5.48 | 0.0430 | 49.4 | 2.12 | 53.0 |
↵* These data are cited from previous report (28) in which uptake of reference compounds (3H-E1S for OATP1B1 and 3H-CCK-8 for OATP1B3) were determined in 3 lots of cryopreserved hepatocytes (lot name: OCF, 094, and ETR).
Relative activity factors for OATP1B1 and OATP1B3 (R1B1 and R1B3, respectively) were defined using uptake of reference compounds in OATP1B1- and OATP1B3-expressing HEK293 cells (OATP1B1- and OATP1B3-HEK, respectively) determined in this study (CL1B1,ref or CL1B3,ref). OATP1B1- and OATP1B3-mediated uptake of SC-62087 in hepatocytes were estimated as product of R1B1 and CL1B1,SC and R1B1 and CL1B1,SC, respectively. Contribution was calculated as ratio of OATP-mediated uptake and CLhepatocyte,SC. Details of calculation are described in “Materials and Methods” section.