[³H]RSV CL_{int,uptake,hep} in SHs, PHs, and SCHHs. [³H]RSV CL_{int,uptake,hep} was determined in four lots of SHs (A), PHs (B), or SCHHs (C). The average contribution to [³H]RSV CL_{int,uptake,hep} followed the order OATPs > NTCP > passive diffusion (D). [³H]RSV CL_{int,uptake,hep}, CL_int,OATP,hep, CL_int,NTCP,hep, and CL_{int,passive,hep} were not significantly different between the hepatocyte models (Wilcoxon matched-pair signed rank test). The average data (Avg) from (A–C) are shown in (D), and they are mean ± S.D. of four lots of hepatocytes, each conducted in triplicate.

IVIVE of RSV hepatic CL_{uptake,in vivo} based on transporter-expressing cells or the hepatocyte models, SHs, PHs, or SCHHs in HBSS buffer (A), or adjusted for the protein-mediated uptake of RSV in transporter-expressing cells (B). The transporter-expressing cells predicted the hepatic CL_{uptake,in vivo} within 3-fold of the observed value (1205.6 ml/min). In contrast, the hepatocyte models underpredicted RSV CL_{uptake,in vivo} by 5- to 10-fold. OATPs were the major contributors to the total RSV CL_{int,in vivo,pred,cells} and CL_{int,in vivo,pred,hep} followed by NTCP, with smallest contributor being passive diffusion CL. The solid and dashed lines show the 95% confidence interval (CI) of the observed hepatic CL_{uptake,in vivo} and 2-fold lower limit of the mean observed hepatic CL_{uptake,in vivo} (603 ml/min). RSV CL_{int,in vivo,pred,cells} was significantly higher (Tukey’s multiple comparison test) than CL_{int,in vivo,pred,hep} obtained from any of the hepatocyte models. Data shown for SH, PH and SCHH are mean ± S.D. of four lots of hepatocytes, each conducted in triplicate. Data shown for transporter-expressing cells are mean ± SD of the predicted values based on transporter abundance in 39 human liver samples. (A) When the transporter-mediated CL_{int,uptake,cells} was adjusted for the increase in the RSV uptake in the presence of 100% HP or 5% HSA, the transporter-expressing cells better predicted hepatic CL_{uptake,in vivo} (595.3 ml/min with 100% HP; 621.4 ml/min in 5% HSA) and came close to or fell just above the lower 2-fold boundary of the observed value (B).

IVCIVH of [³H]RSV CL_{int,uptake,hep}. The predicted [³H]RSV CL_{int,uptake,hep} from transporter-expressing cells was not significantly different from the observed [³H]RSV CL_{int,uptake,hep}, irrespective of whether the predictions were made based on the total or PMA of the uptake transporters. Data shown are mean ± S.D. of four lots of hepatocytes, each conducted in triplicate. NS, not significantly different based on Wilcoxon matched-pair signed rank statistical test.