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Vol. 286, Issue 1, 321-327, July 1998
Department of Pharmacokinetics and Drug Delivery, 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.
0022-3565/98/2861-0321$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics
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