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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

Carter, SJ; Ferecsko, AS; King, L; Menochet, K; Parton, T; Chappell, MJ; (2019) 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. Xenobiotica 10.1080/00498254.2019.1652781. (In press). Green open access

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Abstract

(1) 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. (2) 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. (3) 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. (4) 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.

Type: Article
Title: 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
Open access status: An open access version is available from UCL Discovery
DOI: 10.1080/00498254.2019.1652781
Publisher version: https://doi.org/10.1080/00498254.2019.1652781
Language: English
Additional information: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Mechanistic modelling, micro-rate constant, high throughput, rat hepatocyte uptake, atorvastatin, cyclosporine, metabolism, inhibition mechanism, non-competitive inhibition, competitive inhibition
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10082472
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