title: Cimetidine uptake and interactions with cationic drugs in freshly isolated proximal tubular cells of the rat.
abstract: The uptake of cimetidine was investigated in freshly isolated proximal tubular cells of the rat as well as its interaction with other cationic drugs. The time-dependent uptake of 5 microM cimetidine was linear for 2 min and reached equilibrium after 10 min. The uptake was reduced at 4 degrees C or by addition of 5 mM mepiperphenidol. At pH 7.4, only a small percentage (20%) of cimetidine is present in the cationic form, which is thought to be necessary for transport by the organic cation transporter. At a more acidic pH 6.5, this percentage is increased to 67%, but there was no influence on the cellular uptake in comparison with control. The cationic form of cimetidine does not seem to be a prerequisite for the organic cation transporter in these cells. The uptake of cimetidine was concentration-dependent and saturable. The mepiperphenidol-sensitive uptake had a high (H) and low (L) affinity apparent Km,H of 6.7 +/- 1.2 microM and Km,L of 0.61 +/- 0.16 mM, and Vmax,H of 35.8 +/- 2.2 pmol/mg of protein.min and Vmax,L of 4.5 +/- 0.3 nmol/mg of protein.min. The concentration-dependent inhibition of other cationic drugs on 1 microM cimetidine uptake was investigated. The log concentration-inhibition curves of mepiperphenidol, famotidine and trimethoprim showed a high and low affinity IC50 value, with a potency ranking of mepiperphenidol = famotidine > trimethoprim. The other compounds had only a low affinity IC50 value and the inhibitory potency ranking was as follows: ranitidine = nizatidine > tetraethylammonium > probenecid.
authors.affiliation: Department of Pharmacology, University of Nijmegen, The Netherlands.
authors.forename: S P
authors.initials: SP
authors.lastname: Boom
authors.forename: F G
authors.initials: FG
authors.lastname: Russel
mesh_terms: D000818:Animals; D001692:Biological Transport; D002412:Cations / Q000494:pharmacology*; D002478:Cells, Cultured; D002927:Cimetidine / Q000493:pharmacokinetics* / Q000494:pharmacology; D004347:Drug Interactions; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002412:Cations; D002927:Cimetidine