Consideration of albumin-mediated hepatic uptake for highly protein-bound anionic drugs: Bridging the gap of hepatic uptake clearance between in vitro and in vivo.
Pharmacol Ther
; 229: 107938, 2022 01.
Article
in En
| MEDLINE
| ID: mdl-34171335
ABSTRACT
The accuracy in predicting in vivo hepatic clearance of drugs from in vitro data (often termed as in vitro-to-in vivo extrapolation, IVIVE) has improved in part by applying the extended-clearance concept that considers the interplay between hepatic metabolism and uptake/efflux processes. However, the IVIVE-based prediction performs poorly in predicting the hepatic uptake clearance of highly albumin-bound anionic drugs. Their hepatic uptake clearances tend to be much higher than expected based on the free-drug theory. Such observation can be attributable to a phenomenon called albumin-mediated hepatic uptake, for which various models have been thus far proposed. Our group has been applying a facilitated-dissociation model, which assumes the enhanced dissociation of the drug-albumin complex upon interaction with the cell surface. By considering the albumin-mediated hepatic uptake (using the facilitated-dissociation model or alternative kinetic models), a number of investigations demonstrated the improvement in the prediction accuracy for the hepatic clearance of highly protein-bound anionic drugs that are substrates for hepatic uptake transporters. This review summarizes the reported kinetic analyses of the albumin-mediated hepatic uptake of highly albumin-bound drugs concerning the IVIVE and the clinical and physiological relevance.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Hepatocytes
/
Organic Anion Transporters
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Pharmacol Ther
Year:
2022
Document type:
Article
Affiliation country: