DRUG TRANSPORT IN THE LIVER - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 363

a spectrum of organic anions, bulky (previously called type II) cations, and neutral
steroids. In contrast to NTCP, the OATPs operate in a sodium-independent man-
ner, and some OATP isoforms have been hypothesized to function as glutathione
antiporters, 6 , 7 employing the high intracellular glutathione concentrations as a driv-
ing force for hepatic uptake of substrates with high efficiency. Eleven human OATP
isoforms and 14 rat Oatp isoforms have been identified thus far. A comparison of sub-
strate specificities of Oatps/OATPs between rat and human was published recently 8
and illustrates the discrepancy between rat and human substrate profiles consistent
with the fact that human OATPs are not orthologs of rat Oatps.
OATP1A2, OATP1B1, OATP1B3, and OATP2B1 are the four human OATPs that
are now considered to play a substantial role in hepatic uptake of exogenous and
endogenous compounds at the liver sinusoidal membrane domain. OATP1B1 and
1B3 are liver-specific, whereas OATP2B1 is widely expressed; OATP1A2 exhibits
the highest expression in brain. Despite overlapping substrate specificities (especially
between the 1B1 and 1B3 isoforms), distinct substrate affinity profiles have been
reported. For instance, while all four human liver-expressed OATPs mediate BSP,
dehydroepiandrosterone sulfate (DHEAS), and estrone 3-sulfate transport, bile acids
are reportedly transported by OATP1A2, 1B1, and 1B3, but not by OATP2B1. As
illustrated in Table 13.1, OATP1B1 clearly displays the largest substrate diversity
and appears to have affinity for HMG-CoA reductase inhibitors (“statins”; see Table
13.1). OATP1B1 is the major human liver transport protein that is involved in Na + -
independent bile salt uptake. OATP1B1 also plays a predominant role in hepatic
bilirubin uptake, which was demonstrated by correlating drug-associated inhibition
of OATP1B1-mediated uptake with the incidence of hyperbilirubinemia associated
with these drugs. 9 Interestingly, OATPs also seem to have affinity for several larger-
molecular-weight compounds, such as the lipopeptide antifungal agent caspofungin
(OATP1B1), the cyclic heptapeptide microcystin-LR (OATP1A2, 1B1, 1A3), and the
mushroom toxin phalloidin (OATP1B1 and 1B3). Several substrates were identified
as having selective affinity for just one of the four OATP isoforms expressed in human
liver [e.g., n -methylquinine for OATP1A2; repaglinide and troglitazone sulfate for
OATP1B1; and digoxin, cholecystokinin (CCK)-8, and paclitaxel for OATP1B3].

OATs (SLC22A) Organic anion transporters (OATs) constitute a family of proteins
that mediate transport of primarily negatively charged endogenous and exogenous
compounds in exchange for dicarboxylate ions. Since substantial expression in the
kidney was demonstrated for all human OATs identified and characterized so far
(OAT1-4), the majority of available data regarding OATs has been generated in the
field of renal drug transport. However, OAT2 is expressed predominantly in the si-
nusoidal hepatocyte membrane (with lower expression in basolateral membrane of
proximal kidney tubules). 10 In addition to the earlier identification of prostaglandins,
zidovudine, and tetracycline as OAT2 substrates, a range of structurally dissimilar
compounds (including the drugs taxol, allopurinol and 5-fluorouracil) was recently
added to the OAT2 substrate list (see Table 13.1). 11 The affinity of salicylate for OAT2
remains controversial in that it had been identified as a (weak) substrate in two inde-
pendent studies, 12 , 13

although it clearly could not be classified as a substrate based