Rosuvastatin Liver Partitioning in Cynomolgus Monkeys: Measurement In Vivo and Prediction Using In Vitro Monkey Hepatocyte Uptake.
Unbound plasma concentrations may not reflect those in target tissues, and there is a need for methods to predict tissue partitioning. Here, we investigate the unbound liver partitioning (Kpu,u) of rosuvastatin, a substrate of hepatic organic anion transporting peptides, in cynomolgus monkeys and compare it with that determined using hepatocytes in vitro. Rosuvastatin (3 mg/kg) was administered orally to monkeys and plasma and liver (by ultrasound-guided biopsy) collected over time. Uptake into monkey hepatocytes was evaluated up to steady state. Binding in monkey plasma, liver, and hepatocytes was determined using equilibrium dialysis. Mean in vivo Kpu,u was 118 after correcting total liver partitioning by plasma and liver binding. In vitro uptake data were analyzed by compartmental modeling to determine active uptake clearance, passive diffusion, the intracellular unbound fraction, and Kpu,u. In vitro Kpu,u underpredicted that in vivo, resulting in the need for an empirical in vitro to in vivo scaling factor of 10. Adjusting model parameters using hypothetical scaling factors for transporter expression and surface area or assuming no effect of protein binding on active transport increased partitioning values by 1.1-, 6-, and 9-fold, respectively. In conclusion, in vivo rosuvastatin unbound liver partitioning in monkeys was underpredicted using hepatocytes in vitro. Modeling approaches that allow integrating corrections from passive diffusion or protein binding on active uptake could improve the estimation of in vivo intracellular partitioning of this organic anion transporting peptide substrate. A similar assessment of other active hepatic transport mechanisms could confirm and determine the extent to which limited accumulation in isolated hepatocytes needs to be considered in drug development.
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.).
Bridget L
BL
Morse
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.).
Hong
H
Cai
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.).
Jamus G
JG
MacGuire
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.).
Maxine
M
Fox
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.).
Lisa
L
Zhang
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.).
Yueping
Y
Zhang
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.).
Xiaomei
X
Gu
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.).
Hong
H
Shen
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.).
Elizabeth A
EA
Dierks
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.).
Hong
H
Su
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.).
Chiuwa E
CE
Luk
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.).
Punit
P
Marathe
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.).
Yue-Zhong
YZ
Shu
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.).
W Griffith
WG
Humphreys
Pharmaceutical Candidate Optimization (B.L.M., H.C., L.Z., Y.Z., X.G., H.S., E.A.D., H.S., C.E.L., P.M., Y-Z.S., W.G.H., Y.L.) and Veterinary Sciences, Bristol-Myers Squibb, Princeton, New Jersey (J.G.M., M.F.) yurong.lai@bms.com.
Yurong
Y
Lai
D000818:Animals; D005260:Female; D005544:Forecasting; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D011485:Protein Binding / Q000502:physiology; D000068718:Rosuvastatin Calcium / Q000378:metabolism* / Q000494:pharmacology*
D000068718:Rosuvastatin Calcium