Vol. 286, Issue 1, 321-327, July 1998

Heterologous Expression of Various P-Glycoproteins in Polarized Epithelial Cells Induces Directional Transport of Small (Type 1) and Bulky (Type 2) Cationic Drugs¹

Johan W. Smit, Betty Weert, Alfred H. Schinkel and Dirk K. F. Meijer

Department of Pharmacokinetics and Drug Delivery, University Center for Pharmacy, Groningen Institute for Drug Studies, Groningen (B.W., D.K.F.M.), and Division of Experimental Therapy, The Netherlands Cancer Institute (J.W.S., A.H.S.), Amsterdam, The Netherlands

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 MDR1 gene in confluently grown polarized transformed LLC-PK₁ cells 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.