A mechanistic modelling approach for the determination of the mechanisms of inhibition by cyclosporine on the uptake and metabolism of atorvastatin in rat hepatocytes using a high throughput uptake method. (2nd April 2020)

• Record Type: Journal Article
• Authors: Carter, Simon J.; Ferecskó, Alex S.; King, Lloyd; Ménochet, Karelle; Parton, Ted; Chappell, Michael J.
• Is Part Of: Xenobiotica. Volume 50:Number 4(2020:Apr.)
• Page Start: 415
• Page End: 426
• Publication Date: 2020-04-02
• Subjects: Mechanistic modelling -- micro-rate constant -- high throughput -- rat hepatocyte uptake -- atorvastatin -- cyclosporine -- metabolism -- inhibition mechanism -- non-competitive inhibition -- competitive inhibition; Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.1080/00498254.2019.1652781
• Languages: English
• ISSNs: 0049-8254

Abstract

Abstract: Determine the inhibition mechanism through which cyclosporine inhibits the uptake and metabolism of atorvastatin in fresh rat hepatocytes using mechanistic models applied to data generated using a high throughput oil spin method. Atorvastatin was incubated in fresh rat hepatocytes (0.05–150 nmol/ml) with or without 20 min pre-incubation with 10 nmol/ml cyclosporine and sampled over 0.25–60 min using a high throughput oil spin method. Micro-rate constant and macro-rate constant mechanistic models were ranked based on goodness of fit values. The best fitting model to the data was a micro-rate constant mechanistic model including non-competitive inhibition of uptake and competitive inhibition of metabolism by cyclosporine (Model 2). The association rate constant for atorvastatin was 150-fold greater than the dissociation rate constant and 10-fold greater than the translocation into the cell. The association and dissociation rate constants for cyclosporine were 7-fold smaller and 10-fold greater, respectively, than atorvastatin. The simulated atorvastatin-transporter-cyclosporine complex derived using the micro-rate constant parameter estimates increased in line with the incubation concentration of atorvastatin. The increased amount of data generated with the high throughput oil spin method, combined with a micro-rate constant mechanistic model helps to explain the inhibition of uptake by cyclosporine following pre-incubation.