Review
In vitro–in vivo correlation in p-glycoprotein mediated transport in intestinal absorption

https://doi.org/10.1016/j.ejps.2008.11.005Get rights and content

Abstract

Oral administration is the most common route for drug administration. However, after oral administration, the absorption may be erratic and incomplete. P-glycoprotein, an efflux transporter localized in the enterocyte, limits the absorption of transported drugs extruding them back to the intestinal tract. The interaction between new drug candidates and P-glycoprotein is investigated in vitro during early stages of drug development. However, it is uncertain how well the in vitro studies actually predict the in vivo P-glycoprotein effect on the extent of oral absorption, since the in vitro and in vivo correlation has not been achieved. In the present review, the recent approaches to compare the in vitro and in vivo data are described and parameters are proposed that could be adequate for a reliable in vitro and in vivo correlation of P-glycoprotein contribution on intestinal absorption. The present article identifies an evident lack of suitable in vivo data. A significant in vitro and in vivo correlation would increase the value of in vitro studies and could reduce costs during the process of drug development.

Introduction

Drug development is a very laborious and expensive process. One of the major reasons for failures occurring during the clinical phases of drug development is the inadequate pharmacokinetic properties of the drug candidate. Therefore, it would be advantageous if the pharmacokinetic properties of drug candidates could be predicted beforehand. One major obstacle in making such predictions is the inability to appropriately scale the preclinical in vitro data to the in vivo situation.

The P-glycoprotein (P-gp) is an efflux protein which extrudes a wide variety of chemically different xenobiotics from cells (Mizuno et al., 2003). P-gp is widely expressed in many pharmacokinetic barriers in the body such as intestine, kidney, liver and blood–brain barrier (BBB). Therefore, it may affect significantly the pharmacokinetics of its substrate molecules. For this reason, drug candidates are screened for their interaction with P-gp already during the early stages of drug development (Balimane et al., 2006). There are several in vitro methods used to identify P-gp substrates, though the cell based bidirectional permeability assay is the most popular (Polli et al., 2001). However, the extent to which the in vitro data can predict the impact of P-gp in vivo, remains unclear.

When drugs are delivered via the peroral route, P-gp may limit the intestinal absorption of the therapeutic agent. The purpose of the present review was to examine the in vitro and in vivo data of P-gp on intestinal drug absorption, the in vitro and in vivo correlation (IVIVC) in the literature, and the factors to be taken into account in order to obtain a reliable IVIVC. The in vivo studies selected for this aim were done in P-gp-deficient mouse model: mdr1a(−/−) and mdr1a/1b(−/−) knockout mice and mdr1a(−/−) CF-1 mutant mice.

Section snippets

P-gp structure and mechanism of action

P-gp belongs to the superfamily of ATP-binding cassette transporters (ABC transporters). Humans possess two known P-gp genes, MDR1 (ABCB1) and MDR3 (ABCB4). However, only the MDR1 gene encodes for the multidrug-resistance-related P-gp efflux pump (REFSEQ mRNA: NM_00927.3). In mice, P-gp is encoded by mdr1a (abcb1a) and mdr1b (abcb1b) and mdr2 (abcb4) and the genes that confer the multidrug-resistance phenotype are mdr1a and mdr1b. There is 82% homology of human MDR1 and mouse mdr1a with the

P-gp expression and physiological function

P-gp is over-expressed in many tumor cell lines. In fact it was initially identified in these cell lines (Juliano and Ling, 1976), but it is constitutively expressed also in nearly all barrier tissues of the body (intestine, kidney, liver and BBB).

Human MDR1 P-gp is prominent in the brush border of renal proximal tubules, in the biliary membrane of hepatocytes, in the apical membrane of the epithelial cells in the intestine, in the apical membrane of the capillary endothelial cells of brain and

Oral absorption

The most convenient route of administration of drugs is the peroral route because of the high level of patient safety and acceptance, and relatively low production cost. On the other hand, an oral drug will be therapeutically efficient only if it is absorbed from the gastrointestinal tract and can gain access to the systemic circulation in sufficient quantities. The bioavailability of a drug is defined as the fraction of the dose that appears intact in the systemic circulation. Major efforts

Conclusions

The present review shows the fact that only a few in vivo studies in P-gp-deficient mouse model have been carried out to determine the impact of P-gp on the extent of drug absorption. Moreover, there is a lack of consensus on the protocol of the experiments and the standard in vivo parameter to describe the P-gp function in absorption quantitatively. The ratio F or AQin vivo could serve as such in vivo parameters. However, the possible effects of first pass metabolism and exsorptional

Perspective

In the present review, the lack of a robust IVIVC of P-gp effect in intestinal drug absorption became evident. Better in vivo pharmacokinetic data are required and more specific in vitro parameters need to be calculated in order to determine a potential significant IVIVC. A significant IVIVC would demonstrate the capacity of the in vitro parameter used to predict the effect of intestinal P-gp in vivo. The approaches for IVIVC discussed in the present review are based on in vitro and in vivo

Acknowledgements

This work was financially supported by the Finnish Funding Agency for Technology and Innovation (TEKES).

The authors are associated with Biocenter Kuopio.

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