title: Lack of genetic association between OCT1, ABCB1, and UGT2B7 variants and morphine pharmacokinetics.
abstract: OBJECTIVE
  A high inter-individual variation in the pharmacokinetics and pharmacodynamics of morphine has been observed. Genetic polymorphisms in genes encoding the organic cation transporter isoform 1 (OCT1), the efflux transporter p-glycoprotein (ABCB1), and the UDP-glucuronosyltransferase-2B7 (UGT2B7) may influence morphine pharmacokinetics and thus, also pharmacodynamics. The aim of this study was to evaluate the association between OCT1, ABCB1, and UGT2B7 variants, and morphine pharmacokinetics and -dynamics in healthy volunteers.
  
  
  METHODS
  Pharmacokinetic and pharmacodynamic data were collected from a double-blinded, randomized, crossover trial in 37 healthy subjects. Pharmacokinetic data were analyzed in NONMEM®, and the time-concentration relationship of morphine, morphine-3-glucuronide, and morphine-6-glucuronide was parameterized as the transit compartment rate constant (ktr), clearance (CL), and volume of distribution (VD). The area under the plasma concentration-time curve (AUC0-150min) and the maximum plasma concentration (Cmax) were also calculated. Pharmacodynamic data were measured as pain tolerance thresholds to mechanical stimulation of the rectum and muscle, as well as tonic cold pain stimulation ("the cold pressor test" where hand was immersed in cold water). Six different single nucleotide polymorphisms in three different genes (OCT1 (n=22), ABCB1 (n=37), and UGT2B (n=22)) were examined.
  
  
  RESULTS
  Neither AUC0-150min, ktr, CL, nor VDwere associated with genetic variants in OCT1, ABCB1, and UGT2B7 (all P>0.05). Similarly, the antinociceptive effects of morphine on rectal, muscle, and cold pressor tests were not associated with these genetic variants (all P>0.05).
  
  
  CONCLUSIONS
  In this experimental study in healthy volunteers, we found no association between different genotypes of OCT1, ABCB1, and UGT2B7, and morphine pharmacokinetics and pharmacodynamics. Nonetheless, due to methodological limitations we cannot exclude that associations exist.
authors.affiliation: Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: L M
authors.initials: LM
authors.lastname: Nielsen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: E
authors.initials: E
authors.lastname: Sverrisdóttir
authors.affiliation: Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense, Denmark.
authors.forename: T B
authors.initials: TB
authors.lastname: Stage
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Feddersen
authors.affiliation: Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Brøsen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: L L
authors.initials: LL
authors.lastname: Christrup
authors.affiliation: Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
authors.forename: A M
authors.initials: AM
authors.lastname: Drewes
authors.affiliation: Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark. Electronic address: aneso@rn.dk.
authors.forename: A E
authors.initials: AE
authors.lastname: Olesen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D009020:Morphine / Q000493:pharmacokinetics*; D050811:Octamer Transcription Factor-1 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016032:Randomized Controlled Trials as Topic; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D009020:Morphine; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase
keywords: Healthy volunteers; Interindividual variability; Morphine; Pharmacogenetics; Pharmacokinetics