Human MDR1 and mouse mdr1a P-glycoprotein alter the cellular retention and disposition of erythromycin, but not of retinoic acid or benzo(a)pyrene.

The intracellular concentration of many steroids and xenobiotics is influenced by the membrane protein P-glycoprotein (Pgp). It has been inferred that the intracellular retention of many drugs that upregulate Pgp or modulate Pgp function might also be affected by Pgp. However, the ability of Pgp to influence the translocation of these drugs needs to be established to understand Pgp's influence upon their pharmacological effect. We utilized two approaches to determine the interaction of several agents with Pgp: (a) an in vitro system, LLC-PK1 cell lines and derivative LLC cell lines stably expressing on the apical membrane either mouse mdr1a or human MDR1 Pgp grown as polarized epithelium in transwell culture to measure translocation of radiolabeled drugs; and (b) an in vivo system, mdr1a nullizygous and wild-type animals, to compare the contribution of Pgp to in vivo distribution of radiolabeled drugs. In combination these complementary approaches identified erythromycin as a drug whose intracellular retention is influenced by Pgp, while the intracellular accumulation and tissue distribution of retinoic acid and benzo(a)pyrene were unaffected by Pgp. Copyright 1998 Academic Press.