The Importance of Enterohepatic Recirculation in the Disposition of Pravastatin and Rosuvastatin: A Physiologically-Based Pharmacokinetic Modelling Approach
Sonya C. Tate (1), Hannah M. Jones (2), J. Brian Houston (1) and Aleksandra Galetin (1)
(1) Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, UK; (2) Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Sandwich, UK.
Objectives: The majority of the substrates for hepatic uptake transporters are excreted into the bile to some extent. In the case of non-metabolised substrates pravastatin and rosuvastatin, 63-85% of the dose is excreted into the bile in rat [1], and of this amount 40-50% undergoes enterohepatic recirculation [2, 3]. The current study assesses the inclusion of enterohepatic recirculation in the physiologically-based model and its impact on the prediction of pravastatin and rosuvastatin PK in rat.
Methods: The whole body physiologically-based pharmacokinetic (WBPBPK) model comprised 13 tissues connected in a closed-loop format by arterial and venous blood flow. All non-hepatic tissues assumed perfusion-limited kinetics; hepatic transporter process were incorporated by assuming permeability-limited kinetics for the liver [4-6]. In house in vitro uptake data obtained in rat hepatocytes were used to evaluate hepatic uptake and passive diffusion; biliary clearance was obtained from sandwich cultured hepatocytes [7]. Oral absorption was incorporated into the model using an advanced compartmental transit model [8]; permeability was incorporated using data from the RRCK cell line. Drug eliminated into the bile was considered either to be (a) removed from the body (no recirculation) or (b) to empty into the duodenum and undergo subsequent reabsorption.
Results: The WBPBPK model without recirculation resulted in predicted pravastatin and rosuvastatin i.v. clearances within 1.5-fold of observed data in bile duct-cannulated rats; accumulation in the bile observed was in good agreement with the reported values. The rosuvastatin oral blood AUC tended to be over-predicted in contrast to an under-prediction for pravastatin, in accordance with the over/under-prediction of the i.v. clearances. The model assuming continuous recirculation recovered 55 and 51% of the oral liver AUC for pravastatin and rosuvastatin respectively, compared to the model with no recirculation which provided poorer estimates, with recoveries of 21 and 7%.
Conclusions: The in vitro uptake data provided good estimates of uptake and efflux upon comparison to blood and bile concentrations in bile duct-cannulated rats without the need for empirical scaling factors commonly used in PBPK modelling of uptake substrates in human. The inclusion of enterohepatic recirculation into the WBPBPK model provided more accurate predictions of oral blood and liver profiles than a model assuming no recirculation.
References:
[1] Fukuda, H., et al., Effect of plasma protein binding on in vitro-in vivo correlation of biliary excretion of drugs evaluated by sandwich-cultured rat hepatocytes. Drug Metab Dispos, 2008. 36(7): p. 1275-82.
[2] Nezasa, K., et al., Pharmacokinetics and disposition of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in rat. Xenobiotica, 2002. 32(8): p. 715-27.
[3] Komai, T., et al., Disposition and metabolism of pravastatin sodium in rats, dogs and monkeys. Eur J Drug Metab Pharmacokinet, 1992. 17(2): p. 103-13.
[4] Poirier, A., et al., Prediction of pharmacokinetic profile of valsartan in humans based on in vitro uptake-transport data. Chem Biodivers, 2009. 6(11): p. 1975-87.
[5] Poirier, A., et al., Mechanistic modeling of hepatic transport from cells to whole body: application to napsagatran and fexofenadine. Mol Pharm, 2009. 6(6): p. 1716-33.
[6] Watanabe, T., et al., Physiologically based pharmacokinetic modeling to predict transporter-mediated clearance and distribution of pravastatin in humans. J Pharmacol Exp Ther, 2009. 328(2): p. 652-62.
[7] Abe, K., et al., In vitro biliary clearance of angiotensin II receptor blockers and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in sandwich-cultured rat hepatocytes: comparison with in vivo biliary clearance. J Pharmacol Exp Ther, 2008. 326(3): p. 983-90.
[8] Agoram, B., et al., Predicting the impact of physiological and biochemical processes on oral drug bioavailability. Adv Drug Deliv Rev, 2001. 50 Suppl 1: p. S41-67.