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Apical/Basolateral Surface Expression of Drug Transporters and its Role in Vectorial Drug Transport

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Abstract

It is well known that transporter proteins play a key role in governing drug absorption, distribution, and elimination in the body, and, accordingly, they are now considered as causes of drug–drug interactions and interindividual differences in pharmacokinetic profiles. Polarized tissues directly involved in drug disposition (intestine, kidney, and liver) and restricted distribution to naive sanctuaries (blood–tissue barriers) asymmetrically express a variety of drug transporters on the apical and basolateral sides, resulting in vectorial drug transport. For example, the organic anion transporting polypeptide (OATP) family on the sinusoidal (basolateral) membrane and multidrug resistance-associated protein 2 (MRP2/ABCC2) on the apical bile canalicular membrane of hepatocytes take up and excrete organic anionic compounds from blood to bile. Such vectorial transcellular transport is fundamentally attributable to the asymmetrical distribution of transporter molecules in polarized cells. Besides the apical/basolateral sorting direction, distribution of the transporter protein between the membrane surface (active site) and the intracellular fraction (inactive site) is of practical importance for the quantitative evaluation of drug transport processes. The most characterized drug transporter associated with this issue is MRP2 on the hepatocyte canalicular (apical) membrane, and it is linked to a genetic disease. Dubin–Johnson syndrome is sometimes caused by impaired canalicular surface expression of MRP2 by a single amino acid substitution. Moreover, single nucleotide polymorphisms in OATP-C/SLC21A6 (SLCO1B1) also affect membrane surface expression, and actually lead to the altered pharmacokinetic profile of pravastatin in healthy subjects. In this review article, the asymmetrical transporter distribution and altered surface expression in polarized tissues are discussed.

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Abbreviations

ABC:

ATP-binding cassette

AP:

apical

BBB:

blood–brain barrier

BCRP:

breast cancer resistance protein

BCSFB:

blood–cerebrospinal fluid barrier

BL:

basolateral

BPB:

blood–placenta barrier

BSEP:

bile salt export pump

BSP:

bromosulfophthalein

BTB:

blood–testis barrier

CLAMP:

C-terminal linking and modulating protein

ER:

endoplasmic reticulum

E217βG:

estradiol-17β-d-glucuronide

F-actin:

filamentous actin

HAX-1:

HS1-associated protein X-1

ISBT:

ileal Na+-dependent bile salt transporter

MDR:

multidrug resistance protein

MRP:

multidrug resistance-associated protein

NTCP:

Na+/taurocholate cotransporting polypeptide

OAT:

organic anion transporter

OATP:

organic anion transporting polypeptide

OCT:

organic cation transporter

PEPT:

peptide transporter

PFICII:

progressive familial intrahepatic cholestasis type II

SNP:

single nucleotide polymorphism

UDC:

ursodeoxycholate

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Authors and Affiliations

  1. Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba, Japan

    Kousei Ito & Toshiharu Horie

  2. The University of Tokyo Hospital, Tokyo, Japan

    Hiroshi Suzuki

  3. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, Japan

    Yuichi Sugiyama

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  1. Kousei Ito
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Ito, K., Suzuki, H., Horie, T. et al. Apical/Basolateral Surface Expression of Drug Transporters and its Role in Vectorial Drug Transport. Pharm Res 22, 1559–1577 (2005). https://doi.org/10.1007/s11095-005-6810-2

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