ORGANIC ANION–TRANSPORTING POLYPEPTIDES - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 87

a successful strategy. An example CCK-8, the selective OATP1B3 substrate, is not
only an inhibitor of its transporter but also inhibits the other major hepatic transporter,
OATP1B1. 64 One compound that has been used as a relatively selective OATP1B1
inhibitor to study contribution of various transporters in hepatic drug uptake is E 1 S.
It appears that E 1 S is a far more potent inhibitor of OATP1B1 than OATP1B3. 65 Fur-
thermore, there has been interest in understanding whether certain clinically relevant
drug interactions occur because of OATP inhibition. Many compounds inhibit the
transport activity of the OATPs (Table 5.3), but their inhibitory constants (K i ) range
widely. For instance, drugs such as cyclosporine A, rifampin, and ritonavir have sub-
micromolar inhibitory constants for OATP1B1-mediated uptake and are considered
potent in vitro inhibitors. 66 K i values for OATP-mediated uptake should be used in
context with estimated hepatic drug concentrations to predict clinical drug-interaction
potential. 67

5.5. PHARMACOLOGY AND PHYSIOLOGY OF OATPs

5.5.1. Clinical Pharmacology

The interplay between drug metabolism and transport that occurs locally within tissues
determines overall drug absorption, distribution, and elimination. For many drugs,
particularly those capable of significant diffusion across membranes, the major impact
of drug metabolism overshadows the influence of facilitated membrane transport on
drug disposition. The dynamic, reversible nature of drug transport, as opposed to
drug metabolism, has made it challenging for investigators to understand its role
in pharmacokinetics. Like other transporters, the importance of the OATPs in drug
disposition is most apparent for compounds that are metabolically inert or those
whose rates of metabolism are affected significantly by transporter-mediated delivery
to eliminating enzymes. But similar to the field of drug metabolism, the clinical
relevance of drug transport by the OATPs has begun to emerge from studies that
examine the interindividual variability in drug response caused by genetics and drug
interactions. At present these studies have drawn our attention to roles of OATPs in
intestinal and liver drug disposition, while little has been revealed regarding OATP
functions at the blood-brain-barrier and kidney.

Pharmacogenetics As a potential determinant of interindividual variability in drug
disposition, there has been significant effort in cataloguing polymorphisms in SLCO
genes as well as their frequencies in ethnic populations (Table 5.4). Arguably, the
consequences of polymorphisms in the hepatic uptake transporter OATP1B1 have
received most attention. The cumulative research has shown convincingly that there
exists a few relatively common polymorphisms in SLCO1B1 that are associated with
altered oral drug exposure. One single-nucleotide polymorphism (SNP) is 388A

G
in codon 130, which converts an asparagine residue to aspartate, in the second ex-
tracellular loop of OATP1B1. 38 The frequencies of the SLCO1B1 388G allele ( ∗ 1b)
in Caucasians, African Americans, and Asians is approximately 40, 75, and 60%,
respectively. 38 , 68 − 72

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