Prediction of Cyclosporin-Mediated Drug Interaction Using Physiologically Based Pharmacokinetic Model Characterizing Interplay of Drug Transporters and Enzymes

Abstract

Uptake transporter organic anion transporting polypeptides (OATPs), efflux transporters (P-gp, BCRP and MRP2) and cytochrome P450 enzymes (CYP450s) are widely expressed in the liver, intestine or kidney. They coordinately work to control drug disposition, termed as “interplay of transporters and enzymes”. Cyclosporine A (CsA) is an inhibitor of OATPs, P-gp, MRP2, BCRP and CYP3As. Drug–drug interaction (DDI) of CsA with victim drugs occurs via disordering interplay of transporters and enzymes. We aimed to establish a whole-body physiologically-based pharmacokinetic (PBPK) model which predicts disposition of CsA and nine victim drugs including atorvastatin, cerivastatin, pravastatin, rosuvastatin, fluvastatin, simvastatin, lovastatin, repaglinide and bosentan, as well as drug–drug interactions (DDIs) of CsA with nine victim drugs to investigate the integrated effect of enzymes and transporters in liver, intestinal and kidney on drug disposition. Predictions were compared with observations. Most of the predictions were within 0.5–2.0 folds of observations. Atorvastatin was represented to investigate individual contributions of transporters and CYP3As to atorvastatin disposition and their integrated effect. The contributions to atorvastatin disposition were hepatic OATPs >> hepatic CYP3A > intestinal CYP3As ≈ efflux transporters (P-gp/BCRP/MRP2). The results got the conclusion that the developed PBPK model characterizing the interplay of enzymes and transporters was successfully applied to predict the pharmacokinetics of 10 OATP substrates and DDIs of CsA with 9 victim drugs.

The effects of cyclosporine A or activated charcoal co-administration on the pharmacokinetics of enrofloxacin in chickens

“…CsA affected atorvastatin pharmacokinetics to a larger extent following oral rather than intravenous administration. This effect was mediated by P-gp/BCRP/MRP2-related efflux in addition to CYP3A-mediated metabolism ( Yang et al, 2020 ).…”

Fluorine-18 Labeling of the MDM2 Inhibitor RG7388 for PET Imaging: Chemistry and Preliminary Evaluation

“…However, coincubation of cells with [ 18 F]14 and 50 μM AMG232 resulted in a 10-fold increase in [ 18 F]14 uptake by SJSA-1 cells (20.1 ± 0.3% input dose, p < 0.0001, Figure S19). Furthermore, similarly enhanced cell [ 18 F]14 uptake was observed when SJSA-1 cells were coincubated with 50 μM verapamil or cyclosporine A, suggesting a potential role of efflux transporters (e.g., Pglycoprotein, organic anion transporting polypeptides, CYP3A4) 25,26 in limiting the cellular uptake of [ 18 F]14 at tracer levels. Of note, it has been shown previously that RG7388 is not a good substrate of P-glycoprotein in neuroblastoma cells, 27 which might explain the differences in the results obtained with [ 18 F]6 vs [ 18 F]14.…”

Protein Abundance of Drug Transporters in Human Hepatitis C Livers

“…Velpatasvir is a substrate of P-gp, BCRP, and OATP1B1/1B3 (some 23% of dose metabolized by CYP3A4, 2C8, and 2B6, with minimal renal elimination and some biliary excretion), and its AUC levels (when co-administered with sofosbuvir) increase stepwise in mild (by 9.2%) and moderate (29.9%) HCV-induced hepatic impairment. Co-administration of cyclosporine, a known inhibitor of uptake carrier and efflux transporters, including OATPs, P-gp, MRP2, and BCRP [ 25 ], resulted in AUC increase in the drug by ~two-fold (summarized in [ 26 ]). The studies in hepatic impairment (accessed by Child–Pugh score) in HCV-negative patients with liver cirrhosis, hepatitis B infection, alcoholic liver disease, or previous HCV infection demonstrated an AUC increase in glecaprevir (a substrate of P-gp, BCRP, and OATP1B1/1B3, with about 28% of dose metabolized mostly by CYP3A4, minimal renal and some biliary excretion) (when co-medicated with pibrentasvir) in mild (by 33%), moderate (by 100%), and severe (1010%) hepatic impairment.…”