ORGANIC ANION–TRANSPORTING POLYPEPTIDES - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 91

that in one study the drug levels were clearly different among subject groups. 89 , 90
Larger studies will be required to fully clarify the role of SLCO1B1 polymorphisms
in HMG-CoA reductase inhibitor toxicity and efficacy.
Genetic polymorphisms in SLCO1A2 have been identified and variant proteins
have been characterized in vitro. 13 , 91 (Table 5.5). Few variants are common with

most occurring at a frequency < 10%. One relatively uncommon variant with a fre-

5%, OATP1A1 ∗ 3 (516A

quency of C, Glu172Asp), has reduced transport activity

in vitro as a result from a cell surface trafficking defect. 13 Similarly, genetic varia-
tions in SLCO1B3 have been identified. 92 , 93 (Table 5.5). The 1564G

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> T (Gly522Cys)

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polymorphic variant which is relatively rare ( 2% allelic frequency) in SLCO1B3

when expressed in vitro, has reduced transport function. The influence of SLCO1A2
and SLCO1B3 genetic polymorphisms on drug disposition in vivo remains to be
determined.

Drug Interactions The importance of OATPs in drug disposition has also been made
evident from studies describing drug interactions (Table 5.6). In one study, coad-
ministration of grapefruit juice with fexofenadine resulted in 63% decreased plasma
exposure of the antihistiminic drug. 94 Fexofenadine is a drug that is not apprecia-
bly metabolized and is subject to facilitated membrane transport. That grapefruit
juice was able to effectively inhibit fexofenadine transport mediated by OATP1A2
but not P-glycoprotein suggests that modulation of intestinal OATP1A2 activity was
the mechanism of the drug interaction. Another dramatic drug interaction involving
OATPs is the demonstration that cyclosporine A (CyA) coadministration increased
the plasma exposure of rosuvastatin by sevenfold. 95 Again, rosuvastatin is a drug that
is not metabolized significantly. Since CyA can potently inhibit OATP1B1-mediated
transport of rosuvastatin, 39 , 95 the mechanism for this drug interaction may be inhibi-
tion of hepatic first-pass effect.

TABLE 5.6. Drug Interactions Implicating a Role for OATPs in the Mechanism
OATP

Interacting PK Impact on

Implicated Drug Affected Substance Affected Drug Ref.

OATP1A2 Fexofenadine Grapefruit juice AUC ↓ 63% 94

Fexofenadine Orange juice AUC ↓ 70% 94

Talinolol Grapefruit juice AUC ↓ 44% 156

OATP1B1 Pravastatin Orange juice AUC ↑ 152% 157

Pravastatin Cyclosporine A AUC ↑ Pravachol product

monograph

↑

Pravastatin Gemfibrozil AUC 202% 158

↑

Rosuvastatin Cyclosporine A AUC 710% 95

Rosuvastatin Gemfibrozil AUC ↑ 188% 159

Cerivastatin Cyclosporine A AUC ↑ 3 to 5-fold 160

Cerivastatin Gemfibrozil AUC ↑ 559% 161