CIMETIDINE UPTAKE AND INTERACTIONS WITH CATIONIC DRUGS IN FRESHLY ISOLATED PROXIMAL TUBULAR CELLS OF THE RAT

The uptake of cimetidine was investigated in freshly isolated proximal tubular cells of the rat as well as its interaction with other cation ic drugs. The time-dependent uptake of 5 muM 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 w ith control. The cationic form of cimetidine does not seem to be a pre requisite for the organic cation transporter in these cells. The uptak e of cimetidine was concentration-dependent and saturable. The mepiper phenidol-sensitive uptake had a high (H) and low (L) affinity apparent K(m,H) of 6.7 +/- 1.2 muM and K(m,L) of 0.61 +/- 0.16 mM, and V(max,H ) of 35.8 +/- 2.2 pmol/mg of protein.min and V(max,L) of 4.5 +/- 0.3 n mol/mg of protein.min. The concentration-dependent inhibition of other cationic drugs on 1 muM cimetidine uptake was investigated. The log c oncentration-inhibition curves of mepiperphenidol, famotidine and trim ethoprim showed a high and low affinity IC50 value, with a potency ran king of mepiperphenidol = famotidine > trimethoprim. The other compoun ds had only a low affinity IC50 value and the inhibitory potency ranki ng was as follows: ranitidine = nizatidine > tetraethylammonium > prob enecid.