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.

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 (DDIs) on these processes. After 120 minutes 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, which was followed 120 minutes later by a second bolus of the statin coadministered with OATP perpetrator drug rifampicin (67.7 mg). After 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 coadministration 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: This study 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 these experiments is in good agreement with clinical data, indicating the potential importance of this new ex vivo model in early drug discovery.

Perception of bronchoconstriction in asthma patients measured during histamine challenge test.

This study investigated two aspects of the perception of bronchoconstriction ("sensitivity" and "absolute perceptual magnitude") in asthmatic patients and identified which clinical characteristics are related to these two aspects of perception of bronchoconstriction. The perception of histamine induced bronchoconstriction was measured in 128 asthmatic patients. Subjects quantified their breathlessness on a Visual Analogue Scale (VAS) before forced expiratory volume in one second (FEV1 was measured after each inhalation of histamine. The perceptive "sensitivity" for changes in FEV1 was analysed by the "VAS percentage fall in FEV1" slope. The "absolute perceptual magnitude" was determined by the VAS value at a 20% fall in FEV1. Spearman correlations were used for analysis between the two aspects of perception and asthma symptoms, peak flow variability, bronchial responsiveness and FEV1 % predicted. Patients with a low "sensitivity" for changes in FEV1 were more likely to show a frequent peak flow variability (Rs=-0.21; p<0.05), a high bronchial responsiveness (Rs= 0.37; p<0.001) and a low baseline FEV1 % pred (Rs=0.22; p<0.05). Patient's "absolute perceptual magnitude" correlated positively with symptoms during daily life (significant correlations varied 0.21-0.32) but not with the lung function parameters. The severity of asthma reflected by a low lung function and a high bronchial responsiveness, is associated with a low "sensitivity" for changes in forced expiratory volume in one second. A patient's "absolute perceptual magnitude" is positively related with asthma symptoms during daily life.