Mechanistic Modeling of Pitavastatin Disposition in Sandwich-Cultured Human Hepatocytes: A Proteomics-Informed Bottom-Up Approach.
Drug Metab Dispos
; 44(4): 505-16, 2016 Apr.
Article
em En
| MEDLINE
| ID: mdl-26842596
ABSTRACT
Isolated human hepatocytes are commonly used to predict transporter-mediated clearance in vivo. Such predictions, however, do not provide estimations of transporter contributions and consequently do not allow predictions of the outcome resulting from a change in the activity of a certain transporter, for example, by inhibition or a genetic variant with reduced function. Pitavastatin is a drug that is heavily dependent on hepatic transporters for its elimination, and it is excreted mainly as unchanged drug in the bile. For this reason, pitavastatin was used as a model drug to demonstrate the applicability of a bottom-up approach to predict transporter-mediated disposition in sandwich-cultured human hepatocytes (SCHHs), allowing for the estimation of transporter contributions. Transport experiments in transfected human embryonic kidney cells (HEK293 cell lines) and inverted membrane vesicles overexpressing each of the relevant transport proteins were used to generate parameter estimates for the mechanistic model. By adjusting for differences in transporter abundance between the in vitro systems and individual SCHH batches, the model successfully predicted time profiles of medium and intracellular accumulation. Our predictions of pitavastatin bile accumulation could not be confirmed, however, because of a very low biliary excretion of pitavastatin in relation to the hepatic uptake in our SCHHs. This study is, to our knowledge, the first to successfully simulate transporter-mediated processes in a complex system such as SCHHs at the level of individual transport proteins using a bottom-up approach.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinolinas
/
Técnicas de Cultura de Células
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Inibidores de Hidroximetilglutaril-CoA Redutases
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Hepatócitos
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Proteômica
Tipo de estudo:
Prognostic_studies
Limite:
Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article