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Coexistence of passive and carrier-mediated processes in drug transport

Nature Reviews Drug Discovery volume 9, pages 597–614 (2010)Cite this article

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Abstract

The permeability of biological membranes is one of the most important determinants of the pharmacokinetic processes of a drug. Although it is often accepted that many drug substances are transported across biological membranes by passive transcellular diffusion, a recent hypothesis speculated that carrier-mediated mechanisms might account for the majority of membrane drug transport processes in biological systems. Based on evidence of the physicochemical characteristics and of in vitro and in vivo findings for marketed drugs, as well as results from real-life discovery and development projects, we present the view that both passive transcellular processes and carrier-mediated processes coexist and contribute to drug transport activities across biological membranes.

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Figure 1: The potential of a drug to pass biological membranes by passive and carrier-mediated processes can be assessed by multiple techniques.
Figure 2: Temperature dependency (4 °C and 37 °C) of passive transport through an artificial membrane system of various drugs.
Figure 3: pH-dependent permation of benzoic acid in the rat intestine.
Figure 4: Partitioning versus permeation.
Figure 5: Competition between passive and active transport.
Figure 6: Influence of passive permeation and carrier-mediated efflux on the efflux ratio in Caco-2 cells, described by a theoretical model.

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Acknowledgements

This paper is the joint effort of several colleagues from academia and the pharmaceutical industry working on a topic of common interest. We have to thank all involved colleagues for rapid feedback to support this task. We have to thank H. Kubinyi for comments at the initial phase of this activity.

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Authors and Affiliations

  1. Kiyohiko Sugano is at Pfizer, Research Formulation, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK.,

    Kiyohiko Sugano

  2. Gérgori Gerebtzoff and Frank Senner are at The Non-Clinical Safety Department, Manfred Kansy, Stefanie Bendels, Holger Fischer, F. Hoffmann-La Roche, CH4070 Basel, Switzerland.,

    Manfred Kansy, Stefanie Bendels, Holger Fischer, Grégori Gerebtzoff & Frank Senner

  3. Per Artursson and Hans Lennernaes are at the Department of Pharmacy, Biomedical Centre, Uppsala University, S-752 63 Uppsala, BOX 580, Sweden.,

    Per Artursson & Hans Lennernaes

  4. Alex Avdeef is at pION, 5 Constitution Way, Woburn, Massachussetts 01801, USA.,

    Alex Avdeef

  5. Dynamics and Metabolism Department, Li Di is at the Pharmacokinetics, Pfizer, Groton, Connecticut 06340, USA.,

    Li Di

  6. Gerhard F. Ecker is at the Department of Medicinal Chemistry, University of Vienna, Althanstrasse 141090 Wien, Austria.,

    Gerhard F. Ecker

  7. Bernard Faller is at the Novartis Institutes for Biomedical Research, WSJ350.3.04, CH4002 Basel, Switzerland.,

    Bernard Faller

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  1. Kiyohiko Sugano
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Supplementary information

Supplementary information S1 (Table)

Literatures supporting the evidence of CM transport (PDF 470 kb)

Glossary

Active transport

An energy dependent, carrier protein-mediated transport process that can be against a concentration gradient.

Area under the plasma concentration–time curve

(AUC). A measure of how much of an administered drug reaches the bloodstream in a defined period of time.

Bioavailability

In this article, bioavailability means absolute bioavailability. Bioavailability describes the fraction of an administered dose (unchanged drug) that reaches the systemic circulation. Intravenously administered drugs by definition have a bioavailability of 100%. Other routes of administration may lead to lower bioavailability, usually expressed by a ratio or percentage of the maximum value.

Biopharmaceutics classification system

(BCS). A classification system for drug molecules that considers solubility and permeation. There are four classes: BCS class I (molecules have high permeation/high solubility), BCS class II (molecules have high permeation/low solubility), BCS class III (molecules have low permeation/high solubility) and BCS class IV (molecules have low permeation/low solubility). Secondary factors considered in BCS include the rate of dissolution and the pH.

Black lipid membrane

A single bilayer phospholipid membrane and optically black in appearance. It slowly forms when a small quantity of an egg lecithin dissolved in n-decane is placed over a small hole in a thin sheet of Teflon suspended in an aqueous buffer solution. Such membranes have been viewed as useful models of the more complex natural membranes.

Caco-2 cells

An immortalized line of heterogeneous human epithelial colorectal adenocarcinoma cells used as a drug transport model for assessing intestinal absorption. Transport measurements can be performed in two directions: apical to basolateral or basolateral to apical.

Carrier-mediated transport

This refers to active or facilitated transport that has a limited capacity and thus is saturable and subject to inhibition.

CYP3A4

(Cytochrome P450 3A4). The most important member of the cytochrome P450 mixed-function oxidase system. It is involved in the metabolism of xenobiotics. CYP3A4 metabolism can occur in the gut wall and in the liver.

Efflux ratio

(EfR). The ratio of the apparent permeation of a compound in the absorptive (apical to basolateral) direction to that in the secretory (basolateral to apical) direction, as determined in cell-based experiments. The EfR is used to determine possible active transport.

Fa

The fraction of a dose of drug that is absorbed after oral administration. Fα depends on membrane permeance, solubility and the dissolution rate of a compound. It is expressed as a percentage.

First pass metabolism

After intestinal absorption, drug molecules first pass through the liver before entering the systemic circulation. During this process, the drug can be metabolized in the liver and the systemic bioavailability can be reduced.

Lipophilicity

The affinity of a compound for a lipid environment, for example, the hydrocarbon core of a phospholipid bilayer. It can also be described as the inter-molecular interaction between a compound and the solvent environment, such as the total hydrogen bond strength and dipole/polarizability.

Log Doct

The octanol–water apparent partition coefficient at a certain pH. Both dissociated and undissociated (uncharged) molecular species are taken into account. In this article, when log Doct is less than zero, it is referred to as having low lipophilicity, when log Doct is greater than zero but less than 2, it is referred to as having moderate lipophilicity and when log Doct is greater than 2 it is referred to as having high lipophilicity.

Log Poct

The octanol–water partition coefficient of a compound (neutral form). This parameter is most widely used as a whole molecule lipophilicity parameter.

Oral bioavailability

The fraction or percentage of a drug that reaches the systemic circulation following oral administration. It is determined by the fraction absorbed and the fraction not metabolized in the gut wall and in the liver.

P app

(Permeability coefficient). The apparent permeation for example, in Caco-2 cell-based permeation assays. Papp is the sum of passive transport and carrier-mediated transport when the effect of the aqueous boundary layer and the paracellular pathway is neglected.

Passive transport

This refers to the movement of a permeant across a membrane from a region of high concentration to that of low concentration by a process of diffusion. The rate of passive transport is proportional to the concentration gradient of the permeant across the membrane.

P eff

(Effective intestinal membrane permeation). Peff is measured by an in vivo experiment, for example, the in situ perfusion method. Peff is the sum of passive transport and carrier-mediated transport.

P-glycoprotein

(P-gp). Also called ABCB1, P-gp is a protein involved in active efflux transport processes.

pH partition theory

A theory that describes passive transport based on the pH of the aqueous phase, the dissociation constant (pKa) and the lipophilicity of a permeant. It states that an ionizable drug moves across a membrane by passive diffusion as its uncharged form, depending on its lipophilicity.

pKa

The dissociation constant pKa for an ionizable molecule is the pH at which it would be ionized by 50%. The degree (%) of ionization is pH dependent. For an acid it decreases by lowering pH. For a base it increases by lowering pH.

Tissue distribution coefficient

This represents the degree of drug molecule distributing into a tissue. This value depends on both passive transport and carrier-mediated transport across the cellular membrane of the tissue.

Total permeation

This refers to the combination of passive transport and carrier-mediated transport processes.

Ussing chamber

An instrument used to measure transport (for example, of drugs) across epithelial barriers. A sheet of epithelia (for example, intestinal mucosa) is clamped between two chambers and drug transport across the epithelia is measured.

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Sugano, K., Kansy, M., Artursson, P. et al. Coexistence of passive and carrier-mediated processes in drug transport. Nat Rev Drug Discov 9, 597–614 (2010). https://doi.org/10.1038/nrd3187

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