title: Loss-of-function polymorphisms in the organic cation transporter OCT1 are associated with reduced postoperative tramadol consumption.
abstract: The organic cation transporter OCT1 (SLC22A1) mediates uptake and metabolism of the active tramadol metabolite (+)O-desmethyltramadol in the liver. In this study, the influence of OCT1 genetic polymorphisms on pharmacokinetics and analgesic efficacy of tramadol in patients recovering from surgery was analyzed in addition to the CYP2D6 genotype. Postoperative patients who received tramadol through patient-controlled analgesia were enrolled. Genotypes resulting in 0, 1, or 2 active OCT1 alleles were determined as well as CYP2D6 genotypes. The primary endpoint was the 24-hour postoperative tramadol consumption in patients with 0 vs at least 1 active OCT1 allele. Secondary endpoint was the OCT1-dependent plasma concentration (areas under the concentration-time curves) of the active tramadol metabolite (+)O-desmethyltramadol. Of 205 patients, 19, 82, and 104 carried 0, 1, and 2 active OCT1 alleles, respectively. Cumulative tramadol consumption through patient-controlled analgesia was lowest in patients with 0 active OCT1 allele compared with the group of patients with 1 or 2 active alleles (343 ± 235 vs 484 ± 276 mg; P = 0.03). Multiple regression revealed that the number of active OCT1 alleles (P = 0.014), CYP2D6 (P = 0.001), pain scores (P < 0.001), and the extent of surgery (0.034) had a significant influence on tramadol consumption. Plasma areas under the concentration-time curves of (+)O-desmethyltramadol were 111.8 (95% confidence interval: 63.4-160.1), 80.2 (65.1-95.3), and 64.5 (51.9-77.2) h·ng·mL in carriers of 0, 1, or 2 active OCT1 alleles (P = 0.03). Loss of OCT1 function resulted in reduced tramadol consumption and increased plasma concentrations of (+)O-desmethyltramadol in patients recovering from surgery. Therefore, analyzing OCT1 next to CYP2D6 genotype might further improve future genotype-dependent dose recommendations for tramadol.
authors.affiliation: Department of Anaesthesiology and Pain Medicine, Inselspital, University of Bern, Bern, Switzerland.|Department of Clinical Research, University of Bern, Bern, Switzerland.|Former Affiliation: Department of Anaethesiology and Intensive Care Medicine, University of Bonn, Bonn, Germany.
authors.forename: Ulrike M
authors.initials: UM
authors.lastname: Stamer
authors.affiliation: Department of Forensic Medicine, University of Bonn, Bonn, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Musshoff
authors.affiliation: Department of Anaesthesiology and Pain Medicine, Inselspital, University of Bern, Bern, Switzerland.|Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Frank
authors.initials: F
authors.lastname: Stüber
authors.affiliation: Institute of Clinical Pharmacology, University Medical Center, Göttingen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brockmöller
authors.affiliation: Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Steffens
authors.affiliation: Institute of Clinical Pharmacology, University Medical Center, Göttingen, Germany.
authors.forename: Mladen V
authors.initials: MV
authors.lastname: Tzvetkov
mesh_terms: D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid / Q000097:blood / Q000627:therapeutic use*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D027702:Organic Cation Transporter 1 / Q000235:genetics*; D010149:Postoperative Pain / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020250:Postoperative Nausea and Vomiting / Q000175:diagnosis / Q000209:etiology; D025341:Principal Component Analysis; D012044:Regression Analysis; D013997:Time Factors; D014147:Tramadol / Q000031:analogs & derivatives / Q000097:blood / Q000627:therapeutic use*
chemical_list: D000701:Analgesics, Opioid; D027702:Organic Cation Transporter 1; C080580:O-demethyltramadol; D014147:Tramadol; D019389:Cytochrome P-450 CYP2D6