title: Variability in UDP-glucuronosyltransferase genes and morphine metabolism:  observations from a cross-sectional multicenter study in advanced cancer patients with pain.
abstract: OBJECTIVE
  The objective of the present study was to determine whether genetic variability in UDP-glucuronosyltransferase (UGT) genes, together with clinical factors, contribute to variability in morphine glucuronide (M6G and M3G) to morphine serum concentration ratios in patients with advanced cancer receiving chronic morphine therapy.
  
  
  METHODS
  A total of 41 polymorphisms and predicted haplotypes in the UGT2B7, UGT1A1, and UGT1A8 genes were analyzed in 759 patients who were recruited from the European Pharmacogenetic Opioid Study and received chronic morphine therapy by the oral route (n=635) or parenterally (n=124). The administration groups were analyzed separately by multiple linear regression analyses.
  
  
  RESULTS
  Two haplotypes in UGT1A1/UGT1A8 were weak predictors of reduced M6G/morphine and M3G/morphine serum ratios after oral administration (false discovery rate-corrected P-values<0.1). No effect of genotype was seen in the parenteral group. Of the clinical variables (age, sex, BMI, renal function, Karnofsky performance status, and presence of liver metastases), renal function was the major contributor to variation in serum concentration ratios. Concomitant administration of paracetamol predicted significantly higher morphine metabolic ratios after oral administration of morphine (false discovery rate-corrected P-values<2.1E-12). The regression models explained about 35% of the total variability in the data.
  
  
  CONCLUSIONS
  Genetic variation in the UGT genes together with clinical factors influence morphine metabolic ratios in patients with advanced cancer disease and who are scheduled with oral morphine. This information may be included in future research that develop and test new classification systems for opioid treatment in patients with advanced cancer.
authors.affiliation: Department of Cancer Research and Molecular Medicine, European Palliative Care Research Center, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway. torill.fladvad@ntnu.no
authors.forename: Torill
authors.initials: T
authors.lastname: Fladvad
authors.forename: Pål
authors.initials: P
authors.lastname: Klepstad
authors.forename: Mette
authors.initials: M
authors.lastname: Langaas
authors.forename: Ola
authors.initials: O
authors.lastname: Dale
authors.forename: Stein
authors.initials: S
authors.lastname: Kaasa
authors.forename: Augusto
authors.initials: A
authors.lastname: Caraceni
authors.forename: Frank
authors.initials: F
authors.lastname: Skorpen
mesh_terms: D000368:Aged; D001483:Base Sequence; D003430:Cross-Sectional Studies; D017931:DNA Primers; D005260:Female; D005919:Glomerular Filtration Rate; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000378:metabolism*; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D010146:Pain / Q000209:etiology / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide
chemical_list: D017931:DNA Primers; D009020:Morphine; D014453:Glucuronosyltransferase