The Library
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
Tools
Carter, Simon J., Ferecskó, Alex S., King, Lloyd, Ménochet, Karelle, Parton, Ted and Chappell, Michael J. (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 . doi:10.1080/00498254.2019.1652781 ISSN 1366-5928.
|
PDF
WRAP-mechanistic-modelling-inhibition-cyclosporine-uptake-metabolism-Carter-2019.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution 4.0. Download (2441Kb) | Preview |
Official URL: https://doi.org/10.1080/00498254.2019.1652781
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.
Item Type: | Journal Article | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Subjects: | Q Science > QP Physiology R Medicine > RM Therapeutics. Pharmacology |
|||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Engineering > Engineering | |||||||||
SWORD Depositor: | Library Publications Router | |||||||||
Library of Congress Subject Headings (LCSH): | Liver cells -- Computer simulation, Cyclosporine -- Synthesis -- Inhibitors -- Computer simulation, Statins (Cardiovascular agents) | |||||||||
Journal or Publication Title: | Xenobiotica | |||||||||
Publisher: | Informa UK Limited | |||||||||
ISSN: | 1366-5928 | |||||||||
Official Date: | 19 August 2019 | |||||||||
Dates: |
|
|||||||||
DOI: | 10.1080/00498254.2019.1652781 | |||||||||
Status: | Peer Reviewed | |||||||||
Publication Status: | Published | |||||||||
Access rights to Published version: | Open Access (Creative Commons) | |||||||||
Date of first compliant deposit: | 27 September 2019 | |||||||||
Date of first compliant Open Access: | 27 September 2019 | |||||||||
RIOXX Funder/Project Grant: |
|
|||||||||
Related URLs: |
Request changes or add full text files to a record
Repository staff actions (login required)
View Item |
Downloads
Downloads per month over past year