Pharmacogenetic aspects of tramadol pharmacokinetics and pharmacodynamics after a single oral dose.
The major purpose of this study was to elucidate if genotyping can facilitate interpretations of tramadol (TRA) in forensic case work, with special regard to the estimation of the time of drug intake and drug related symptoms (DRS). The association between genetic polymorphisms in CYP2D6, OPRM1 and ABCB1 and pharmacokinetic and pharmacodynamic properties of TRA was studied. Nineteen healthy volunteers were randomized into two groups receiving a single dose of either 50 or 100mg of orally administrated TRA. Blood samples were collected prior to dosing and up to 72h after drug intake. The subjects were asked to report DRS during the experimental day. We found a positive correlation between the metabolic ratio of O-desmethyltramadol (ODT) to TRA and the time after drug intake for both CYP2D6 intermediate metabolizers and extensive metabolizers. For the only poor metabolizer with detectable ODT levels the metabolic ratio was almost constant. Significant associations were found between the area under the concentration-time curve (AUC) and three of the investigated ABCB1 single nucleotide polymorphisms for TRA, but not for ODT and only in the 50mg dosage group. There was great interindividual variation in DRS, some subjects exhibited no symptoms at all whereas one subject both fainted and vomited after a single therapeutic dose. However, no associations could be found between DRS and investigated polymorphisms. We conclude that the metabolic ratio of ODT/TRA may be used for estimation of the time of drug intake, but only when the CYP2D6 genotype is known and taken into consideration. The influence of genetic polymorphisms in ABCB1 and OPRM1 requires further study.
Department of Medical and Health Sciences, Division of Drug Research, Linköping University, Linköping, Sweden.
Salumeh
S
Bastami
Department of Medical and Health Sciences, Division of Drug Research, Linköping University, Linköping, Sweden; National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
Pernilla
P
Haage
Department of Medical and Health Sciences, Division of Drug Research, Linköping University, Linköping, Sweden; National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
Robert
R
Kronstrand
Department of Medical and Health Sciences, Division of Drug Research, Linköping University, Linköping, Sweden; National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
Fredrik C
FC
Kugelberg
National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden. Electronic address: anna-lena.zackrisson@rmv.se.
Anna-Lena
AL
Zackrisson
Department of Clinical and Experimental Medicine, Linköping University, Department of Clinical Chemistry, County Council of Östergötland, Linköping, Sweden.
Srinivas
S
Uppugunduri
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000284:Administration, Oral; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D053803:Forensic Genetics; D053593:Forensic Toxicology; D005838:Genotype; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011897:Random Allocation; D017450:Receptors, Opioid, mu / Q000235:genetics*; D014147:Tramadol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000701:Analgesics, Opioid; C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; C080580:O-demethyltramadol; D014147:Tramadol; D019389:Cytochrome P-450 CYP2D6
ABCB1; CYP2D6; OPRM1; Pharmacodynamics; Pharmacokinetics; Tramadol