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.

Autor: Carter SJ; Biomedical and Biological Systems Laboratory, School of Engineering, University of Warwick, Coventry, United Kingdom., Ferecskó AS; UCB Pharma Ltd, Slough, United Kingdom., King L; UCB Pharma Ltd, Slough, United Kingdom., Ménochet K; UCB Pharma Ltd, Slough, United Kingdom., Parton T; Mekinopsis Ltd, London, United Kingdom., Chappell MJ; Biomedical and Biological Systems Laboratory, School of Engineering, University of Warwick, Coventry, United Kingdom.
Jazyk: angličtina
Zdroj: Xenobiotica; the fate of foreign compounds in biological systems [Xenobiotica] 2020 Apr; Vol. 50 (4), pp. 415-426. Date of Electronic Publication: 2019 Aug 19.
DOI: 10.1080/00498254.2019.1652781
Abstrakt: 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.
Databáze: MEDLINE
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