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In Vivo Characterization of Interactions on Transporters

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Transporters in Drug Development

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 7))

Abstract

Drug transporters play indispensable roles in the disposition of drugs in the body; e.g., in hepatic and renal eliminations, intestinal absorption, and in transport across active barriers, and consequently, in the response to drugs. Importance of the solute carrier family, such as OATP/SLCO, OCT/SLC22, OAT/SLC22, and MATE/SLC47, and the ATP-binding cassette transporters, such as P-glycoprotein/ABCB1, MRPs/ABCC, and BCRP/ABCG2, are well recognized in drug discovery and clinical situations. To date, it is however a great challenge to identify in vivo probe substrates and inhibitors applicable for investigating the impact of drug transporters in humans. This chapter has summarized the relevant clinical drug–drug interaction and pharmagenomic studies on drug transporters in humans, as well as some in vitro studies on transporters, in order to suggest applicable probe substrates and inhibitors for drug transporters. In addition to the drugs at the market, some endogenous and food-derived metabolites are probes for drug transporters. This chapter also highlights the impact of drug transporters on such compounds.

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Abbreviations

ABC:

ATP-binding cassette

AUC:

Area under the plasma concentration–time curve

BBB:

Blood–brain barrier

BCRP:

Breast cancer resistance protein

CLoverall :

Overall intrinsic clearance

CLr :

Renal clearance

CLT :

Total body clearance

CNS:

Central nervous system

CR:

Clearance ratio (ratio of renal clearance to the glomerular filtration)

DDI:

Drug–drug interaction

F h :

Hepatic availability

f p :

Unbound fraction in plasma

GFR:

Glomerular filtration rate

MATE:

Mutlidrug and toxic compound extrusion

MRP:

Multidrug-resistant associated protein

NMN:

N-methylnicotinamide

NTCP:

Sodium bile acid co-transporting polypeptide

OAT:

Organic anion transporter

OATP:

Organic anion transporting polypeptide

OCT:

Organic cation transporter

PET:

Positron emission tomography

P-gp:

P-glycoprotein

PSeff :

The clearance for the back flux

PSinf :

The clearance for the influx

RAF:

Relative activity factor

SLC:

Solute carrier

SNP:

Single nucleotide polymorphism

SPECT:

Single photon emission computed tomography

TEA:

Tetraethyl ammonium

TIC:

(15R)-16-m-tolyl-17, 18, 19, 20-tetranorisocarbacyclin

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Acknowledgement

The authors would like to thank Dr. Mari Miyajiam and Sumito Ito for their kind support.

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Authors and Affiliations

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

    Hiroyuki Kusuhara, Kenta Yoshida & Yuichi Sugiyama

  2. Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Research Cluster for Innovation, RIKEN, Tsurumi-ku, Yokohama, Japan

    Yuichi Sugiyama

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  1. Hiroyuki Kusuhara
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  2. Kenta Yoshida
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Correspondence to Hiroyuki Kusuhara .

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Editors and Affiliations

  1. The University of Tokyo Graduate School of Pharmac. Sciences, Tokyo, Japan

    Yuichi Sugiyama

  2. Pharma, Drug Transporters in ADME Department of Pharmacy, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark

    Bente Steffansen

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Kusuhara, H., Yoshida, K., Sugiyama, Y. (2013). In Vivo Characterization of Interactions on Transporters. In: Sugiyama, Y., Steffansen, B. (eds) Transporters in Drug Development. AAPS Advances in the Pharmaceutical Sciences Series, vol 7. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8229-1_4

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