CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 788

specificity as OATP1B1, but there are some differences in affinity. 600 Moreover, in
contrast to OATP1B1, unconjugated bilirubin is not a substrate for OATP1B3. 601 In
addition, OATP1B3 has also been reported to transport leukotriene C 4 , linear and
cyclic peptides, the intestinal peptide cholecystokinin 8 (CCK-8), digoxin, ouabain,
and deltorphin II. 602 , 603
OATP1C1 has narrower substrate specificity: T4 (thyroxine) and reverse T3 (re-
verse triiodothyronine) are the highest affinity substrates, whereas BSP, steroid sul-
fates and conjugates, and T3 are transported to a lesser extent. 591 Analogously,
OATP4A1 exerts high affinity for T4, T3, and reverse T3, but it was also found
to transport taurocholate, steroid sulfates and conjugates, prostaglandin E 2 , and
benzylpenicillin. 599 , 604 Although there is wide tissue distribution, the substrate speci-
ficity of OATP2B1 is rather limited. OATP2B1 substrates include BSP and steroid
sulfates (e.g., estrone 3-sulfate and dehydroepiandrosterone sulfate), whereas con-
trasting results have been reported for steroid conjugates and prostaglandin E 2 . 591 , 602
To date, less is known about OATP4C1 substrate specificity. OATP4C1 has been
reported to transport cardiac glycosides (digoxin and ouabain), thyroid hormones
(triiodothyronine and thyroxine), cAMP, and methotrexate in a sodium-independent
manner. 605

Inhibitors (Competitive, Noncompetitive) Several compounds have been reported
to inhibit OATP activity. Cyclosporin has been shown to inhibit OATP1B1 in vivo,
thus modulating the pharmacokinetics of repaglinide, a novel antidiabetic drug. 606
The antimicrobial rifamycin SV was able to strongly block OATP1B1-, OATP1B3-,
OATP2B1-, and OATP1A2-mediated transport of BSP in vitro and in vivo, whereas
rifampicin, a drug structurally related to rifamycin SV, was shown to inhibit in a com-
petitive manner OATP1B3 primarily, and to a lesser extent, OATP1B1, in preclinical
and clinical studies. 607 , 608 Rifamycin SV and rifampicin decreased BSP clearance in
humans significantly and were shown to interfere with OATPs-mediated estradiol-
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-glucuronide transport, probably through inhibition of OATPs-mediated hepatic
uptake. Moreover, rifamycin SV and rifampicin were shown to interfere with hep-
atic organic anion uptake by inhibition of Oatp1a1 and Oatp1a4 in rats. Inhibition of
OATPs transport activity by rifamycin antibiotics has been suggested to determine the
reduced hepatic bilirubin/organic anion elimination observed during initial treatment
with these antimicrobial agents. 607 - 610
Recently, grapefruit, orange, and apple juices as well as several of their
furanocoumarin, bioflavonoid, and bergamottin constituents (such as 6 ,7 -
dihydroxybergamottin, bergamottin, naringin, hesperidin, methoxypsoralen) were re-
ported to reduce human OATP and rat Oatp activity in vitro and in vivo, thus leading
to clinically relevant drug-food interactions. 139 , 611 For instance, in a clinical study
performed in 12 healthy volunteers, grapefruit juice at a commonly consumed vol-
ume diminished the oral bioavailability of coadministered fexofenadine sufficiently
to be clinically relevant. The main molecular mechanism of this interaction could be
the direct inhibition mediated by grapefruit juice on the intestinal OATP1A2 uptake
of fexofenadine. 612 Analogously, the antimicrobials ketoconazole and erythromycin