RT Journal Article
SR Electronic
T1 Prediction of Transporter-Mediated Rosuvastatin Hepatic Uptake Clearance and Drug Interaction in Humans Using Proteomics-Informed REF Approach
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 159
OP 168
DO 10.1124/dmd.120.000204
VO 49
IS 2
A1 Kumar, Vineet
A1 Yin, Mengyue
A1 Ishida, Kazuya
A1 Salphati, Laurent
A1 Hop, Cornelis E.C.A.
A1 Rowbottom, Christopher
A1 Xiao, Guangqing
A1 Lai, Yurong
A1 Mathias, Anita
A1 Chu, Xiaoyan
A1 Humphreys, W. Griffith
A1 Liao, Mingxiang
A1 Nerada, Zsuzsanna
A1 Szilvásy, Nóra
A1 Heyward, Scott
A1 Unadkat, Jashvant D.
YR 2021
UL http://dmd.aspetjournals.org/content/49/2/159.abstract
AB Suspended, plated, or sandwich-cultured human hepatocytes are routinely used for in vitro to in vivo extrapolation (IVIVE) of transporter-mediated hepatic clearance (CL) of drugs. However, these hepatocyte models have been reported to underpredict transporter-mediated in vivo hepatic uptake CL (CLuptake,in vivo) of some drugs. Therefore, we determined whether transporter-expressing cells (TECs) can accurately predict the CLuptake,in vivo of drugs. To do so, we determined the uptake CL (CLint,uptake,cells) of rosuvastatin (RSV) by TECs (organic anion transporting polypeptides/Na+-taurocholate cotransporting polypeptide) and then scaled it to that in vivo by relative expression factor (REF) (the ratio of transporter abundance in human livers and TEC) determined by liquid chromatography tandem mass spectrometry–based quantitative proteomics. Both the TEC and hepatocyte models did not meet our predefined success criteria of predicting within 2-fold the RSV CLuptake,in vivo value obtained from our positron emission tomography (PET) imaging. However, the TEC performed better than the hepatocyte models. Interestingly, using REF, TECs successfully predicted RSV CLint,uptake,hep obtained by the hepatocyte models, suggesting that the underprediction of RSV CLuptake,in vivo by TECs and hepatocytes is due to endogenous factor(s) not present in these in vitro models. Therefore, we determined whether inclusion of plasma (or albumin) in TEC uptake studies improved IVIVE of RSV CLuptake,in vivo. It did, and our predictions were close to or just fell above our lower 2-fold acceptance boundary. Despite this success, additional studies are needed to improve transporter-mediated IVIVE of hepatic uptake CL of drugs. However, using REF and TEC, we successfully predicted the magnitude of PET-imaged inhibition of RSV CLuptake,in vivo by cyclosporine A.SIGNIFICANCE STATEMENT We showed that the in vivo transporter-mediated hepatic uptake CL of rosuvastatin, determined by PET imaging, can be predicted (within 2-fold) from in vitro studies in transporter-expressing cells (TECs) (scaled using REF), but only when plasma proteins were included in the in vitro studies. This conclusion did not hold when plasma proteins were absent in the TEC or human hepatocyte studies. Thus, additional studies are needed to improve in vitro to in vivo extrapolation of transporter-mediated drug CL.