Oxybutynin and trospium are substrates of the human organic cation transporters

Abstract

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.

Variability and Heritability of Thiamine Pharmacokinetics With Focus on OCT1 Effects on Membrane Transport and Pharmacokinetics in Humans

“…In humans, OCT1 shows strong expression in the sinusoidal membrane of hepatocytes and only minor, if any, expression in other organs . OCT1 can be relevant for the hepatic uptake and pharmacokinetics of numerous drugs, including metformin, morphine, O‐desmethyltramadol, sumatriptan, fenoterol, trospium, and ranitidine . Beyond that, OCT1 may also be relevant for hepatic uptake of numerous naturally occurring cations, including dopamine, epinephrine, serotonin, tyramine, and thiamine .…”

Effect of Concomitant Administration of Trospium Chloride Extended Release on the Steady-State Pharmacokinetics of Metformin in Healthy Adults

“…Both metformin and trospium are substrates of the proximal gut cation transporter system [23, 24]. Our hypothesis is that metformin has a higher affinity/efficiency of absorption compared with trospium chloride and, therefore, competition between metformin and trospium for the transporter limits absorption of trospium from the intestine when the two drugs are coadministered.…”

“…Human OCTs (hOCTs) are involved in both the intestinal absorption and renal and/or hepatic elimination of metformin (hOCT 1,2 ) and trospium (hOCT 1,2,3 ), and could contribute to their active tubular and hepatobiliary secretion [23, 24]. Consequently, it is possible that transport of one or both of these agents might be inhibited by the administration of the other agent, thus affecting their absorption and/or elimination.…”

Early Discontinuation of Metformin in Individuals Treated with Inhibitors of Transporters of Metformin

“… We conducted subgroup analyses in strata of (a) age, (b) gender and (c) Charlson comorbidity index. We applied alternative outcome definitions as proxies of ‘metformin intolerance’: (a) failing to fill a second prescription within the first 365 days after index date (up from 180) and (b) failing to fill a second prescription within 180 days but filling a prescription for another antidiabetic drug within the same time window. We applied alternative definitions of exposure to potentially interacting drugs: (a) changing the time window for the drug from 120 prior to index date to 90 and 180 days; (b) requiring another prescription filled within the first 120 days after the index date in addition to the prescription filled prior to the index date; and (c) at least three prescriptions redeemed of the exposure drug within the 2 years prior to the index date and one prescription within the 120 days prior to the index date to ensure chronic use of the exposure drug. If metformin acts as the perpetrator in interactions with other drugs, this might lead to cessation of metformin treatment, which might be misconstrued as metformin intolerance. To assess this, we performed an analysis in which we excluded users of drugs that might be negatively affected by metformin use, namely topiramate (N03AX11) , vitamin K‐antagonists (B01AA) , trospium (G04BD09) and aliskiren (C09XA02) . …”

“…4 If metformin acts as the perpetrator in interactions with other drugs, this might lead to cessation of metformin treatment, which might be misconstrued as metformin intolerance. To assess this, we performed an analysis in which we excluded users of drugs that might be negatively affected by metformin use, namely topiramate (N03AX11) [33], vitamin K-antagonists (B01AA) [34][35][36], trospium (G04BD09) [37,38] and aliskiren (C09XA02) [39].…”