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Industrial Evaluation of Drug Transporters in ADME

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Transporters in Drug Development

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

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Abstract

To date, more than 400 absorptive and exsorptive membrane transporters have been identified in the human genome, many of which have been characterized and are known to be important from the perspective of pharmaceutical development. Determining the relative importance of these transporters and their influence on drug disposition, therapeutic efficacy and safety, e.g., drug–drug interactions, has been the focus of considerable research, both in academia and the pharmaceutical industry. The interaction of a drug with transporters can potentially lead to alterations in exposure, resulting in toxicity or in certain instances therapeutic failure. For scientists working in the pharmaceutical industry, the importance of understanding drug–transporter interactions is critical as evidenced by the inclusion of drug transporters in recent regulatory guidances. Transporter scientists at Boehringer Ingelheim provide experimental data and an expert interpretation of these data to project teams and work collaboratively with all supporting functions in efforts to determine the potential clinical impact.

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Abbreviations

ABC:

ATP-binding cassette

ADME:

Absorption, distribution, metabolism, excretion

BBB:

Blood–brain barrier

BCRP:

Breast cancer resistance protein

BCS:

Biopharmaceutics Classification System

BSA:

Bovine serum albumin

CLr:

Renal clearance

CNS:

Central nervous system

CNT:

Concentrative nucleoside transporter

CYP450:

Cytochrome P450 enzyme

D :

Dose

DDI:

Drug–drug interaction

DIN:

Drug interaction number

DME:

Drug metabolizing enzyme

DMPK:

Drug metabolism and pharmacokinetics

ENT:

Equilibrative nucleoside transporter

EoPhII:

End of Phase 2

FDA:

US Food and Drug Administration

Fu:

Fraction unbound

GFR:

Glomerular filtration rate

hADME:

Human absorption, distribution, metabolism, and excretion study

HCV:

Hepatitis C virus

I :

Inhibitor

[I]:

Inhibitor concentration

[I 2]:

Inhibitor concentration in the gastrointestinal tract

IC50 :

Concentration at which 50 % inhibition occurs

ITC:

International Transporter Consortium

K i :

Dissociation constant of the transporter-inhibitor complex for competitive inhibition

K m :

Michaelis-Menten constant, substrate concentration at which the rate is half maximal

KO:

Knockout animal model

LC-MS/MS:

Liquid chromatography, tandem mass spectrometry

M&S:

Modeling and simulation

MATE:

Multidrug and toxin extrusion transporter

MDR1:

Multidrug resistance protein 1

MRP (1/2/3):

Multidrug resistance associate protein (1/2/3)

NCE:

New chemical entity

NDA:

New Drug Application

NTCP:

Sodium taurocholate co-transporting polypeptide

OAT(1/3):

Organic anion transporter (1/3)

OATP(1B1/1B3):

Organic anion transporting polypeptide (1B1/1B3)

OCT2:

Organic cation transporter 2

OCTN:

Organic cation transporter, novel

Papp:

Apparent membrane permeability

PBPK:

Physiologically based pharmacokinetic modeling

P-gp:

P-glycoprotein

PGx:

Pharmacogenomics

PK:

Pharmacokinetics

PoC:

Proof of Concept

R&D:

Research and development

S :

Substrate

SGLT-2:

Sodium-dependent glucose transporter 2

SLC:

Solute carrier protein

SNP:

Single nucleotide polymorphism

SoPD:

Start of pre-development

SoPhI/II/III:

Start of clinical Phase I, II, or III

SUR1:

Sulfone urea transporter 1

TR-M1/2:

Transporter milestone meeting 1 and 2

V g :

Volume of the gastrointestinal fluid

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Authors and Affiliations

  1. Boehringer Ingelheim Pharmaceuticals: Drug Metabolism and Pharmacokinetics, Ridgefield, CT, USA

    Mitchell E. Taub Ph.D. & Donald J. Tweedie

  2. Kobe Pharma Research Institute, Kobe, Japan

    Naoki Ishiguro & Olaf Schaefer

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  1. Mitchell E. Taub Ph.D.
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  2. Naoki Ishiguro
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  3. Olaf Schaefer
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  4. Donald J. Tweedie
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Correspondence to Mitchell E. Taub Ph.D. .

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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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© 2013 Springer Science+Business Media New York

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Taub, M.E., Ishiguro, N., Schaefer, O., Tweedie, D.J. (2013). Industrial Evaluation of Drug Transporters in ADME. 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_12

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