TY - JOUR T1 - Heterologous Expression of Various P-Glycoproteins in Polarized Epithelial Cells Induces Directional Transport of Small (Type 1) and Bulky (Type 2) Cationic Drugs JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 321 LP - 327 VL - 286 IS - 1 AU - Johan W. Smit AU - Betty Weert AU - Alfred H. Schinkel AU - Dirk K. F. Meijer Y1 - 1998/07/01 UR - http://jpet.aspetjournals.org/content/286/1/321.abstract N2 - We recently showed that absence of mdr1-type P-glycoprotein (P-gp) in mice resulted in profoundly reduced hepatic and intestinal clearance of type 1 and type 2 cationic drugs compared with that in wild-type mice. These data strongly support the concept that mdr1-type P-gps are involved in the disposition of cationic amphiphilic drugs from the body. We tested the hypothesis that mdr1-type P-gps are involved in the transmembrane transport of organic cations in epithelial cells expressing various drug-transporting P-gps. Therefore, transepithelial transport of the P-gp substrate vinblastine, the steroidal (type 2) cation vecuronium, the relatively small (type 1) cationic compound azidoprocainamide methoiodide and the aliphatic cation tri-n-butylmethylammonium were measured. Apical expression of the mdr1a, mdr1b or MDR1gene in confluently grown polarized transformed LLC-PK1cells resulted in highly enhanced apical directed secretion of all the drugs tested compared with controls. The vectorial transport of tri-n-butylmethylammonium in the apical direction in the P-gp (over)expressing cells could be inhibited by vinblastine. The present observations show that apical secretion of type 1 as well as of type 2 organic cations is enhanced significantly in the presence of apical expressed mdr1-type P-gp. These findings provide evidence for the involvement of drug-transporting P-gp in transmembrane transport of various organic cations, including relatively small molecular weight aromatic and aliphatic compounds. The American Society for Pharmacology and Experimental Therapeutics ER -