Rosuvastatin Liver Partitioning in Cynomolgus Monkeys: Measurement In Vivo and Prediction Using In Vitro Monkey Hepatocyte Uptake

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Bridget L MorseYurong Lai

Abstract

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 ...Continue Reading

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Citations

Feb 26, 2016·The Journal of Pharmacology and Experimental Therapeutics·Hong ShenYurong Lai
Jul 16, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Keith RiccardiLi Di
Apr 8, 2017·Journal of Pharmaceutical Sciences·Julia RiedeBirk Poller
May 4, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Tom De BruynJ Brian Houston
Jan 25, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Cen XieFrank J Gonzalez
Mar 4, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Julia RiedeGian Camenisch
Mar 5, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Keith RiccardiLi Di
Nov 28, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Bridget L MorseKathleen M Hillgren
Oct 11, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Xiaomin LiangYurong Lai

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