Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes.
The influence of CYP2D6 genotype and CYP2D6 inhibitors on enantiomeric plasma levels of tramadol and O-desmethyltramadol as well as response to tramadol was investigated. One hundred and seventy-four patients received one hundred intravenous tramadol 3 mg/kg for postoperative analgesia. Blood samples drawn 30, 90, and 180 min after administration were analyzed for plasma concentrations of the enantiomers (+)-, (-)tramadol and (+)-, (-)O-desmethyltramadol by liquid chromatography-tandem mass spectrometry. Different CYP2D6 genotypes displaying zero (poor metabolizer (PM)), one (heterozygous individual (HZ)/intermediate metabolizer (IM)), two extensive metabolizer (EM), and three (ultra rapid metabolizer (UM)) active genes were compared. Concentrations of O-desmethyltramadol differed in the four genotype groups. Median (1/3 quartile) area under the concentration-time curves for (+)O-desmethyltramadol were 0 (0/11.4), 38.6 (15.9/75.3), 66.5 (17.1/118.4), and 149.7 (35.4/235.4) ng x h/ml for PMs, HZ/IMs, EMs, and UMs (P<0.001). Comedication with CYP2D6 inhibitors decreased (+) O-desmethyltramadol concentrations (P<0.01). In PMs, non-response rates to tramadol treatment increased fourfold compared with the other genotypes (P<0.001). In conclusion, CYP2D6 genotype determined concentrations of O-desmethyltramadol enantiomers and influenced efficacy of tramadol treatment.
Stamer
U M
UM
Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Bonn, Germany. ulrike.stamer@ukb.uni-bonn.de
Musshoff
F
F
Kobilay
M
M
Madea
B
B
Hoeft
A
A
Stuber
F
F
D000328:Adult; D000368:Aged; D016058:Analgesia, Patient-Controlled; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement; D010149:Postoperative Pain / Q000517:prevention & control*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry; D014147:Tramadol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome
D000701:Analgesics, Opioid; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; C080580:O-demethyltramadol; D014147:Tramadol; D019389:Cytochrome P-450 CYP2D6