CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 787

increased exposure to pravastatin due to a decreased uptake of the statins from blood
into hepatocytes in subjects carrying these haplotypes has been suggested to en-
hance the risk of myotoxic effects. On the other hand, as statins reduce cholesterol
levels primarily by inhibiting the hepatic HMG-CoA reductase, a reduction of the
cholesterol-lowering efficacy of pravastatin could be predicted. 581 In contrast, the
haplotype 130AspVal174, was reported to increase the hepatic OATP1B1-dependent
uptake of pravastatin, thus putatively contributing to lower oral bioavailability of this
statin (by reducing its AUC after oral administration), other analog drugs, and possi-
bly valsartan and temocapril, two widely used drugs transported by OATP1B1. 585 , 586
Analogously, certain OATP1B1 variant haplotypes have been found to reduce the up-
take from blood into hepatocytes of pitavastatin, a new HMG-CoA reductase inhibitor
in healthy Korean volunteers. 982 Allelic variants of OATP1B1 have been reported
to affect the pharmacokinetics of repaglinide, an antidiabetic drug transported by
OATP1B1. 587 These findings support the hypothesis that SNPs in OATPs may influ-
ence the interindividual variability in disposition and drug response in the population.
Genetic polymorphism in the SLCO1B3 and SLCO2B1 genes has been studied,
and several SNPs have been identified. A complete functional characterization of these
variants is required to assess their possible implications for drug disposition. 583 , 588
In addition, several OATP1A2 SNPs were identified in the Japanese population, and
some of them were located in regulatory regions of the SLCO1A2 gene. As OATP1A2
is localized predominantly in the capillary endothelial cells of the brain, allelic variants
of OATP1A2 could affect the brain distribution and toxicity of several substrate
drugs. 502 , 589

Main Substrate Classes (Clinically Applied) In general, OATPs mediate the trans-
port of structurally diverse compounds such as organic anions, cations, neu-
tral or zwitterionic substances, and certain peptidomimetic agents. The principal
OATP physiological substrates are bile acids, bilirubin, steroids, thyroid hormones,
prostaglandins, and cholecystokinine. An increasing number of clinically used drugs
has been recognized to be transported by OATPs. OATP substrate drugs include several
HMG-CoA reductase inhibitors, and in particular, pravastatin, the antihistaminergic
compound fexofenadine, the angiotensin-converting enzyme inhibitors enalapril and
temocaprilat, the cardiac glycoside digoxin, the antidiabetic repaglinide, the folate
analog methotrexate, the endothelin receptor antagonist BQ-123, and several antimi-
crobial agents, such as benzylpenicillin and rifampin.
In particular, OATP1A2 has a broad substrate specificity and has been reported to
transport bile salts and bromosulfophtalein (BSP), steroid sulfates, thyroid hormones
[triiodothyronine (T3), thyroxine (T4), and reverse T3], prostaglandin E 2 , fexofena-
dine, opioid peptides [e.g., deltorphin II and ( d -penicillamine)enkephalin], rocuro-
nium, N -methylquinine and N -methylquinidine, ouabain, the endothelin receptor an-
tagonist BQ-123, the thrombin inhibitor CRC-220, and certain magnetic resonance
imaging contrast agents. 122 , 590 - 594 OATP1B1 substrates include bile salts, conjugated
and unconjugated bilirubin, BSP, steroid conjugates, T3 and T4, peptides, natural tox-
ins such as microcystin and phalloidin, and drugs such as pravastatin, methotrexate,
benzylpenicillin, and rifampicin. 595 - 599 OATP1B3 displays similar broad substrate