Resolution of P‐glycoprotein and non‐P‐glycoprotein effects on drug permeability using intestinal tissues from mdr1a (−/−) mice

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Abstract
Intestinal xenobiotic transporters are a significant barrier to the absorption of many orally administered drugs. P‐glycoprotein (PGP) is the best known, but several others, including members of the multidrug resistance‐associated protein (MRP) family, are also expressed. Definitive information on their precise effect on intestinal drug permeability is scarce due to a lack of specific inhibitors and the difficulty of studying non‐PGP activity in the presence of high PGP expression. We have investigated the in vitro use of intestinal tissues from PGP knockout (mdr1a (−/−)) mice as a tool for dissecting the mechanisms of intestinal drug efflux. The permeability characteristics of digoxin (DIG), paclitaxel (TAX) and etoposide (ETOP) were measured in ileum from mdr1a (−/−) and wild‐type (FVB) mice mounted in Ussing chambers. DIG and TAX exhibited marked efflux across FVB tissues (B‐A : A‐B apparent permeability (Papp) ratio 10 and 17 respectively) which was absent in mdr1a (−/−) tissues, confirming that PGP is the sole route of intestinal efflux for these compounds. The A‐B Papp of both compounds was 3 – 5 fold higher in mdr1a (−/−) than in FVB. Polarized transport of ETOP in FVB tissues was reduced but not abolished in mdr1a (−/−) tissues. Residual ETOP efflux in mdr1a (−/−) tissues was abolished by the MRP inhibitor MK571, indicating involvement of both PGP and MRP. MK571 abolished calcein efflux in mdr1a (−/−) tissues, while quinidine had no parallel effect in FVB tissues, suggesting involvement of MRP but not PGP. Tissues from mdr1a (−/−) mice provide a novel approach for investigating the influence of PGP ablation on intestinal permeability and for resolving PGP and non‐PGP mechanisms that modulate drug permeability. British Journal of Pharmacology (2002) 135, 2038–2046; doi:10.1038/sj.bjp.0704668

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