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Pharmacokinetic Drug-Drug Interactions Between Trospium Chloride and Ranitidine Substrates of Organic Cation
Bayew Tsega Abebe1, Michael Weiss2, Christiane Modess1
1Department of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine of Greifswald, Greifswald, Germany.
Abstract:
Trospium chloride, a muscarinic receptor blocker, is poorly absorbed with different rates from areas in the jejunum and the cecum/ascending colon. To evaluate whether organic cation transporter (OCT) 1, OCT2 and multidrug and toxin extrusion (MATE) 1 and MATE2-K are involved in pharmacokinetics, competitions with ranitidine, a probe inhibitor of the cation transporters, were evaluated in transfected HEK293 cells. Furthermore, a drug interaction study with trospium chloride after intravenous (2 mg) and oral dosing (30 mg) plus ranitidine (300 mg) was performed in 12 healthy subjects and evaluated by noncompartmental analysis and population pharmacokinetic modeling. Ranitidine inhibited OCT1, OCT2, MATE1, and MATE2-K with half maximal inhibitory concentration values of 186 ± 25 µM, 482 ± 105 µM, 134 ± 37 µM, and 35 ± 11 µM, respectively. In contrast to our hypothesis, coadministration of ranitidine did not significantly decrease oral absorption of trospium. Instead, renal clearance was lowered by ∼15% (530 ± 99 vs 460 ± 120 mL/min; P < .05). It is possible that ranitidine was not available in competitive concentrations at the major colonic absorption site, as the inhibitor is absorbed in the small intestine and undergoes degradation by microbiota. The renal effects apparently result from inhibition of MATE1 and/or MATE2-K by ranitidine as predicted by in vitro to in vivo extrapolation. However, all pharmacokinetic changes were not of clinical relevance for the drug with highly variable pharmacokinetics. Intravenous trospium significantly lowered mean absorption time and relative bioavailability of ranitidine, which was most likely caused by muscarinic receptor blocking effects on intestinal motility and water turnover.
Insights
Ranitidine did not affect trospium chloride oral absorption but reduced renal clearance by inhibiting organic cation transporters (OCTs) and multidrug and toxin extrusion (MATE) proteins. Trospium chloride impacted ranitidine
Area of Science:
- Pharmacology
- Drug Metabolism and Transporter Studies
Background:
- Trospium chloride, a muscarinic receptor antagonist, exhibits variable absorption across the gastrointestinal tract.
- The involvement of organic cation transporters (OCTs) and multidrug and toxin extrusion (MATE) proteins in trospium chloride pharmacokinetics is not fully understood.
Purpose of the Study:
- To investigate the role of OCT1, OCT2, MATE1, and MATE2-K in trospium chloride's pharmacokinetic profile.
- To evaluate potential drug-drug interactions between trospium chloride and ranitidine, a known inhibitor of cation transporters.
Main Methods:
- In vitro assessment of ranitidine's inhibitory effects on OCT1, OCT2, MATE1, and MATE2-K in transfected HEK293 cells.
- A clinical drug interaction study involving intravenous and oral administration of trospium chloride with ranitidine in healthy subjects.
- Pharmacokinetic analysis using noncompartmental and population modeling.
Main Results:
- Ranitidine demonstrated inhibitory activity against OCT1, OCT2, MATE1, and MATE2-K in vitro.
- Coadministration of ranitidine did not significantly alter the oral absorption of trospium chloride.
- Ranitidine significantly reduced trospium chloride's renal clearance by approximately 15%, attributed to MATE1/MATE2-K inhibition.
- Intravenous trospium chloride administration affected ranitidine's absorption and bioavailability, likely due to anticholinergic effects on gastrointestinal motility.
Conclusions:
- While ranitidine inhibits key cation transporters in vitro, its clinical impact on trospium chloride oral absorption is minimal.
- Ranitidine's inhibition of MATE1 and/or MATE2-K leads to a modest decrease in trospium chloride renal clearance.
- Observed pharmacokinetic changes are unlikely to be clinically significant given trospium chloride's inherent pharmacokinetic variability.
- Trospium chloride can influence ranitidine pharmacokinetics through its effects on gastrointestinal motility.
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