ORGANIC ANION–TRANSPORTING POLYPEPTIDES - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 84

5.4. OATP SUBSTRATES AND INHIBITORS
5.4.1. Substrates
As a whole, members of the OATP superfamily are broadly selective transporters
interacting with solutes with diverse characteristics (Table 5.3). OATP substrates are
relatively large and range in size from 334 Da (benzylpenicillin) to 1143 Da (cholecys-
tokinin octapeptide, CCK-8). Some common features of OATP substrates are steroidal
or peptidic (linear or cyclic) structural templates. Generally, solutes transported by
OATPs are negatively charged, but there are several examples of neutral (digoxin) and
cationic ( N -methylquinine) substrates. Several drug classes are susceptible to trans-
port by OATPs and those include 3-hydroxy-3-methylglutarylcoenzyme A (HMG-
CoA) reductase inhibitors (statins), angiotensin II receptor antagonists, angiotensin
converting enzyme inhibitors, and cardiac glycosides. The endogenous substrates for
OATPs are hormones such as thyroxine and steroid conjugates, bile acids, bilirubin,
and prostaglandins. In the absence of structural data, the understanding of molecular
determinants of substrates in their interactions with the OATPs has been learned on
the basis of three-dimensional quantitative structure-activity relationship and phar-
macophore modeling approaches. 62 , 63 These studies support the requirement of a
hydrophobic region and hydrogen acceptor and donors for OATP substrates.
5.4.2. Substrate Specificity of OATPs
Many OATPs share common substrates. For example, estrone 3-sulfate (E 1 S) can
be considered somewhat of a pan-substrate for OATPs. But it is quite apparent that
there are clear differences among the OATPs in substrate specificity (Table 5.3).
Certainly, CCK-8 seems to be solely transported by OATP1B3. Among the members
of the superfamily, OATP1A2 possesses perhaps the broadest spectrum of solutes
in that compounds of acidic, basic, and neutral character are substrates. Most other
OATPs appear to have a predilection for acidic, amphipathic solutes. Why certain
compounds have propensities for transport by specific OATPs remains an area of
much interest, particularly since isoform-specific substrates could be used as chemical
tools to interrogate the activity of OATPs in vivo and complex in vitro systems such
as primary cells.
5.4.3. Inhibitors
As with substrates, inhibitors of OATPs can be useful tools to study the pharma-
cological and physiological impact of this transporter superfamily in vivo and in
vitro. Selective inhibitors of OATPs have been sought, especially to understand the
relative contribution of each hepatic OATP in drug clearance. However, the use of
isoform-specific substrates to identify selective OATP inhibitors has not yet been