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Transporters in Drug Development pp 23–35Cite as

In Vitro Kinetic Characterization of Transporter-Mediated Permeability

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

Abstract

Permeability studies across cells or tissue are often applied to investigate for permeability being rate limiting in bioavailability. In addition permeability of drug substances/candidates is investigated in order to identify transport mechanism across the cells or tissues, i.e., by passive diffusion and/or by membrane transport proteins. Characterization of transport mechanism is important in order to elucidate if permeability could be altered/dose-dependent as drug substance/candidate is interacting on saturable transporters. In the present chapter is described how especially transporter-mediated permeability may be studied in vitro exemplified by using E1S as probe. Furthermore, it is speculated upon if E1S can be used as biomarker, in vivo, for the identification of possible clinical effects of drug substances/candidates interacting on transporter(s) which E1S is substrate for and it is suggested that future studies should elucidate such possibilities.

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Notes

  1. 1.

    Refers to the single hydroxyl functionality in the third position of the steroid molecule. Thus, the abbreviation E1 is used to differentiate E1 from the other estrogens, estradiol (E2) and estriol (E3), which contain 2 and 3 hydroxyl functionalities, respectively. The sulfonic acid ester of E1 is named estrone-3-sulfate to indicate that the sulfonic acid ester is in the third position of the steroid molecule and for this reason E1S is also sometimes abbreviated as E3S. In the present chapter, however, the abbreviation E1S is applied.

Abbreviations

ADME:

Absorption, distribution metabolism and elimination

BCRP:

Breast cancer resistance protein

C 0 :

Initial donor concentration

DDI:

Drug–drug interactions

E1 :

Estrone

E1S:

Estrone-3-sulfate

E2 :

Estradiol

[I]:

Inhibiting drug substance/candidate concentration

IC50 :

Drug substance/candidate concentration at which 50 % inhibition occurs

I max :

Maximal inhibitory effect of the drug substance/candidate

IVIVC:

In vitro–in vivo correlation

J :

Flux

J max :

Maximal carrier-mediated flux

K i :

Inhibitory affinity constant

K m :

Michaelis–Menten-derived substrate affinity constant

MATE 1/2-K:

Multidrug and toxin extrusion 1/2-K

MRP 1/2:

Multidrug resistance protein 1/2

NTCP:

Na+/taurocholate cotransporting polypeptide

OAT 3/4:

Organic anion transporter 3/4

OATP 1A2/1B1/1B3/2B1/3A1/4A1:

Organic anion transporting protein

OSTα/β:

Organic solute transporter α/β

OSTα/β:

Organic solute transporter α/β

PAPP:

Apparent transcellular permeability

P Pas :

Passive permeability

P UP :

Uptake permeability

SLC:

Solute carrier

SOAT:

Sodium-dependent organic anion transporter

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Authors and Affiliations

  1. Faculty of Health and Medical Sciences, Drug Transporters in ADME, Department of Pharmacy, University of Copenhagen, 2 Universitetsparken, Copenhagen, 2100, Denmark

    Bente Steffansen M.Sc. (pharm), Ph.D. & Anne Sophie Grandvuinet

Authors
  1. Bente Steffansen M.Sc. (pharm), Ph.D.
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  2. Anne Sophie Grandvuinet
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Correspondence to Bente Steffansen M.Sc. (pharm), 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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Steffansen, B., Grandvuinet, A.S. (2013). In Vitro Kinetic Characterization of Transporter-Mediated Permeability. 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_2

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