Oxybutynin and trospium are substrates of the human organic cation transporters

The muscarinic antagonists oxybutynin and trospium are used as spasmolytic agents for the treatment of overactive urinary bladder disease. Recently, it has been shown that trospium, but not oxybutynin, is a substrate of the multidrug efflux carrier P-glycoprotein, but carrier-mediated drug uptake has not been directly analysed for both drugs. However, trospium has been previously shown to exhibit inhibitory potency for the organic cation transporters (OCTs). The aim of the present study was to examine whether trospium and oxybutynin are substrates, i.e. are transported by the human OCTs (hOCT 1 , hOCT 2 and hOCT 3 ). Therefore, we measured total and specific (decynium-22-sensitive) uptake, and saturation kinetics of the uptake for [ 3 H]oxybutynin and [ 3 H]trospium in human embryonic kidney (HEK293) cells transiently transfected with the cDNA of hOCT 1 , hOCT 2 or hOCT 3 . In addition, we determined IC 50 values for inhibition of hOCT-mediated [ 3 H]MPP + uptake by unlabelled trospium and oxybutynin. Total uptake of [ 3 H]oxybutynin was very high in all transfected HEK293 cells and only a small portion was due to specific, decynium-22-sensitive hOCT-mediated uptake. Oxybutynin inhibited [ 3 H]MPP + uptake by the three hOCTs with IC 50 values between 20 and 130 μM. Direct determination of transport kinetics was measurable only at hOCT 1 with K m of 8 μM and V max of 484 pmol/mg protein/min. The rank order of affinity (1/IC 50 or 1/ K m ) of specific oxybutynin uptake was hOCT 1 > hOCT 2 = hOCT 3 . The observed high non-specific uptake is obviously a consequence of the high lipophilicity of this uncharged drug. Thus, hOCTs may not play a significant role for the overall pharmacokinetics and tissue distribution of oxybutynin. However, and in contrast to oxybutynin, uptake of [ 3 H]trospium, an organic cation, was mainly due to carrier-mediated uptake by the three hOCTs. With IC 50 values of 18, 1.4 and 710 μM (at hOCT 1 , hOCT 2 and hOCT 3 , respectively) and K m values of 17 and 8 μM and about identical V max values of about 90 pmol/mg protein/min at hOCT 1 and hOCT 2 , respectively; the rank order of affinity (1/IC 50 or 1/ K m ) of specific uptake of trospium was hOCT 2 > hOCT 1 > > hOCT 3 . Thus, hOCTs very probably contribute to the active tubular and hepatobiliary secretion of trospium. Furthermore, hOCT 1 and hOCT 3 may be involved in the tissue uptake of this drug in the urinary bladder.