Abstract
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.
Footnotes
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Send reprint requests to: Johan W. Smit, Division of Experimental Therapy (H6), The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
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↵1 Part of this work has been presented at the FEBS advanced lecture course “ATP binding cassette (ABC) transporters: from multidrug resistance to genetic disease,” GOSAU, Aut. (22/2/97–1/3/97).
- Abbreviations:
- mdr/MDR
- multidrug resistance
- P-gp
- P-glycoprotein
- APM
- azidoprocaiamide methoiodide
- TBuMA
- tri-n-butylmethylammonium
- APDA
- azo-pentyl-deoxyajmalinium
- OCT
- organic cation transporter
- OATP
- organic anion transporting polypeptide
- Received November 19, 1997.
- Accepted March 27, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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