10/30/2017 - Role of transporters in drug ADME

Successful prediction of in vivo hepatobiliary clearances and hepatic concentrations of rosuvastatin using sandwich-cultured rat hepatocytes, transporter-expressing cell lines, and quantitative proteomics

Ishida K,Ullah M, Toth B, Juhasz V, Unadkat JD.

Drug Metab Dispos. 2017 Oct 30. pii: dmd.117.076539. doi: 10.1124/dmd.117.076539. [Epub ahead of print]

PMID: 29084782


We determined whether in vivo transporter-mediated hepatobiliary clearance and hepatic concentrations of rosuvastatin (RSV) in the rat could be predicted by transport activity in sandwich-cultured rat hepatocytes (SCRH) and/or transporter-expressing cell lines scaled by differences in transporter protein expression between SCRH, cell lines, and rat liver. The predicted hepatobiliary clearances and hepatic concentrations of RSV were compared to our previously published PET imaging data. Sinusoidal uptake clearance (CLs,uptake) and efflux (canalicular and sinusoidal) clearances of [3H]-RSV in SCRH were evaluated in the presence and absence of Ca2+ and in the absence and presence of 1 mM unlabeled RSV (to estimate passive diffusion clearance). CLuptake of RSV into cells expressing Organic anion transporting polypeptide (Oatp) 1a1, 1a4, and 1b2 was also determined. Protein expression of Oatps in SCRH and Oatp-expressing cells was quantified by LC-MS/MS. SCRH well predicted the in vivo RSV sinusoidal and canalicular efflux clearances, but significantly underestimated in vivo CLs,uptake Oatp expression in SCRH was significantly lower than that in the rat liver. CLs,uptake, based on RSV CLuptake into Oatp-expressing cells (active transport) plus passive diffusion clearance in SCRH , scaled by the difference in protein expression in Oatp cells vs. SCRH vs. rat liver, was within the 2-fold of that observed in SCRH or in vivoIn vivo hepatic RSV concentrations were well predicted by Oatp-expressing cells after correcting CLs,uptake for Oatp protein expression. This is the first demonstration of successful prediction of in vivo hepatobiliary clearance and hepatic concentrations of RSV using transporter-expressing cells and SCRH.

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