Evaluation of Normothermic Machine Perfusion of Porcine Livers as a Novel Preclinical Model to Predict Biliary Clearance and Transporter-mediated Drug-Drug Interactions using Statins

Evaluation of Normothermic Machine Perfusion of Porcine Livers as a Novel Preclinical Model to Predict Biliary Clearance and Transporter-mediated Drug-Drug Interactions using Statins

Stevens, L.J.
Zhu, A.Z.X.
Chothe, P.P.
Chowdhury, S.K.
Donkers, J.M.
Vaes, W.H.J.
Knibbe, C.A.J.
Alwayn, I.P.J.
van de Steeg, E.

2021

There is a lack of translational preclinical models that can predict hepatic handling of drugs. In this study we aimed to evaluate the applicability of normothermic machine perfusion (NMP) of porcine livers as a novel ex vivo model to predict hepatic clearance, biliary excretion and plasma exposure of drugs. For this evaluation we dosed atorvastatin, pitavastatin and rosuvastatin as model drugs to porcine livers and studied the effect of common drug-drug interactions (DDI) on these processes. After 120 min of perfusion, 0.104 mg atorvastatin (n=3), 0.140 mg pitavastatin (n=5) or 1.4 mg rosuvastatin (n=4) was administered to the portal vein, 120 min later followed by a second bolus of the statin co-administrated with OATP perpetrator drug rifampicin (67.7 mg). Following the first dose, all statins were rapidly cleared from the circulation (hepatic extraction ratio > 0.7) and excreted into the bile. Presence of human specific atorvastatin metabolites confirmed the metabolic capacity of porcine livers. The predicted biliary clearance of rosuvastatin was found to be closer to the observed biliary clearance. A rank-order of the DDI between the various systems upon co-administration with rifampicin could be observed: atorvastatin (AUC Ratio 7.2)> rosuvastatin (AUC Ratio 3.1)> pitavastatin (AUC Ratio 2.6) which is in good agreement with the clinical DDI data. The results from this study demonstrated the applicability of using NMP of porcine livers as a novel preclinical model to study OATP-mediated DDI and its effect on hepatic clearance, biliary excretion and plasma profile of drugs. Significance Statement In this study we evaluated the use of normothermic machine perfusion(NMP) of porcine livers as a novel preclinical model to study hepatic clearance, biliary excretion, plasma (metabolite) profile of statins and OATP-mediated DDI. Results showed that NMP of porcine livers is a reliable model to study OATP-mediated DDI. Overall, the rank order of DDI severity indicated in our experiments is in good agreement with clinical data, indicating the potential importance of this new ex vivo model in early drug discovery.

Biliary excretion
Drug-drug interactions
Isolated perfused liver
Organic anion uptake / efflux (OATs, OATPs)

http://resolver.tudelft.nl/uuid:c4cf7f58-3aca-4583-906b-411380009071

https://doi.org/10.1124/dmd.121.000521

958129

Drug Metabolism and Disposition, 49 (49), 780-789

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