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 in fluenced by the membrane protein P-glycoprotein (Pgp). It has been inf erred that the intracellular retention of many drugs that upregulate P gp or modulate Pgp function might also be affected by Pgp. However, th e ability of Pgp to influence the translocation of these drugs needs t o be established to understand Pgp's influence upon their pharmacologi cal effect. We utilized two approaches to determine the interaction of several agents with Pgp: (a) an in vitro system, LLC-PK1 cell lines a nd 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 com pare the contribution of Pgp to in vivo distribution of radiolabeled d rugs. In combination these complementary approaches identified erythro mycin as a drug whose intracellular retention is influenced by Pgp, wh ile the intracellular accumulation and tissue distribution of retinoic acid and benzo(a)pyrene were unaffected by Pgp. (C) 1998 Academic Pre ss.