Relevance of basolateral efflux in published studies
HEPATIC BASOLATERAL EFFLUX CONTRIBUTES
SIGNIFICANTLY TO ROSUVASTATIN DISPOSITION
In a paper published in 2013, researchers from the
University of North Carolina studied and established
the importance of basolateral efflux in the clearance of
rosuvastatin, using rat and human hepatocytes.1 This study
was the first to specifically examine the role of basolateral
transporters in the hepatobiliary disposition of rosuvastatin.
The researchers found that basolateral efflux was
approximately equal to the canalicular efflux. This study has
added to the growing interest in the scientific community
regarding the importance of basolateral efflux in the in vivo
disposition of drugs and metabolites.
SPECIES DIFFERENCES IN HEPATOBILIARY DISPOSITION
OF TAUROCHOLIC ACID IN HUMAN AND RAT SANDWICH-CULTURED
In a paper published in 2015, researchers from the University
of North Carolina used pharmacokinetic modeling to evaluate
species differences in the hepatic transport of taurocholic
acid in order to better understand bile acid homeostasis and
its implications for drug-induced liver injury.2 The basolateral
clearance for taurocholic acid was approximately 25-30% of
the canalicular clearance, and is likely mediated by MRP3 and
MRP4 basolateral transport.
Both of these examples clearly highlight the importance of
basolateral efflux and its emergence as a competing and
compensatory mechanism of clearance. Inhibitory effects
of a drug on bile acid transport mediated by multiple efflux
pathways (basolateral and canalicular) should be considered
when evaluating the hepatotoxic potential of drugs.
In addition, using transporter-impaired systems such as
suspension hepatocytes or unproven and inaccurate methodologies
that combine basolateral and biliary efflux together
will result in grossly overestimated hepatic clearance data and
generally inaccurate conclusions.