Genetically modified mouse models for oral drug absorption and disposition
Section snippets
The problem of intestinal drug absorption
Intestinal absorption is an essential factor in the therapeutic use of virtually all orally administered drugs. Given its importance, it is surprising how little is clearly established about the transmembrane transport processes involved. Almost every oral drug that needs to act systemically has to pass at least two membranes: the apical and basolateral membranes of the enterocytes (Figure 1). Only very small, hydrophilic drugs can pass the tight junction barrier between the enterocytes. All
Equilibrative nucleoside transporter 1 (Ent1)
The equilibrative nucleoside transporter 1 (Ent1; Slc29a1) belongs to the nucleoside transporter family (Slc29). It can transport endogenous nucleosides bidirectionally across plasma membranes, probably by a facilitated diffusion mechanism dependent on the transmembrane electrochemical gradient of the substrate [1]. In the human intestinal tract, ENT1 is concentrated predominantly in the lateral membrane of crypt cells, but it is also found in the lateral and apical membranes of more
Organic cation transporters (Oct) 1 and 2 (Slc22a1 and a2)
The organic cation transporters Oct1 and 2 are thought to be passive diffusion transporters for a diverse range of organic cations. Transport direction of substrates is thus dependent on their electrochemical gradient across the membrane. Contradictory evidence in the literature suggests that Oct1 is located either at the apical or at the basolateral membrane of enterocytes, while Oct2 is located at the basolateral membrane of polarized cells [5••, 6]. mRNA of these transporters is strongly
Organic cation transporters Octn1 and Octn2 (Slc22a4 and a5)
In contrast to Oct1 and Oct2, Octn1 and Octn2 are usually located at the apical membrane of epithelial cells (Figure 1) and mRNA is strongly expressed in the kidney. mRNA expression is also observed in various tissues such as liver, muscles and brain. In the small intestine of rodents, both Octn1 and Octn2 are substantially expressed in the apical membrane of enterocytes [6, 9]. Both transport the zwitterion L-carnitine and a variety of other organic cations and zwitterions including several
Intestinal efflux transporters P-glycoprotein (Abcb1a/1b) and Breast cancer resistance protein (Abcg2)
Both these ATP-binding cassette (ABC) efflux transporters reside in the apical membrane of enterocytes, and have a very wide substrate spectrum. They can therefore actively pump many orally administered substrate drugs and other xenobiotics back into the intestinal lumen, thus reducing their oral availability (Figure 1). These important functions as uncovered with knockout mouse models have been extensively reviewed before, and we refer to the article by Dr. Fromm and colleagues [11] in this
Multidrug resistance-associated protein 2 (Mrp2, Abcc2)
The multidrug resistance-associated protein 2 (Mrp2, Abcc2) is also an ABC drug efflux transporter for many drugs and drug conjugates. It is expressed in the apical membrane of enterocytes (Figure 1), where it could potentially reduce the intestinal absorption of drug substrates [13]. As Abcc2 is also expressed in the bile canalicular membrane and in the apical membrane of renal proximal tubular cells it can contribute substantially to the systemic clearance of its substrates, which may affect
Multidrug resistance-associated protein 3 (Mrp3, Abcc3)
Abcc3 is another ABC drug efflux transporter, capable of transporting bile acids [18] and endogenous glucuronide conjugates [19]. Unlike Abcc2, Abcc3 is expressed in the basolateral membrane of hepatocytes and enterocytes [19, 20, 21], where it mediates the basolateral efflux of substrates either from enterocytes or hepatocytes into the blood (Figure 1). With respect to xenobiotics, Abcc3 is active in the basolateral efflux of a broad range of glucuronides [22], sulfates [23], folates [24],
Multidrug resistance-associated protein 4 (Mrp4, Abcc4)
The ABC drug efflux transporter Abcc4 can extrude a wide variety of endogenous organic anions and xenobiotics out of the cell, including steroid and bile acid conjugates [26], diuretics [27], antibiotics [28] and antiviral drugs [29]. Its subcellular localization is cell-type dependent: apical in renal proximal tubular epithelial cells, but basolateral in prostate tubuloacinar cells, hepatocytes, and choroid plexus epithelium [30]. It is not exactly clear where Abcc4 resides in the intestine.
Organic anion-transporting polypeptides (OATP, SLCO) OATP1A and OATP1B
Organic anion-transporting polypeptides (Oatps, Slco) are Na+-independent transmembrane transporters that mediate the cellular uptake of a broad range of organic endogenous and exogenous compounds, including many drugs and their conjugates [34]. Human OATP1A2 and human and mouse OATP2B1 are thought to be located in the apical membrane of enterocytes, where they could have an important role in intestinal uptake of drugs. In addition, mouse Oatp1a4 and Oatp1a5 mRNAs were detected in small
Conclusion
Unlike the situation for several apical intestinal efflux transporters, that clearly limit the intestinal uptake of drugs, insight into the intestinal transporters that facilitate intestinal drug absorption is still surprisingly limited. Ongoing and future studies with genetically modified mouse models may further improve these insights, thus supporting the development of optimal orally available drugs.
Conflict of interest
The research group of A.H. Schinkel receives revenue from commercial distribution of some of the mouse strains discussed in this review.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgement
This work was supported in part by an academic staff training scheme fellowship from the Malaysian Ministry of Higher Education.
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These authors contributed equally to this paper.