Morphine glucuronide-to-morphine plasma ratios are unaffected by the UGT2B7 H268Y and UGT1A1*28 polymorphisms in cancer patients on chronic morphine therapy

Eur J Clin Pharmacol. 2002 Aug;58(5):353-6. doi: 10.1007/s00228-002-0490-1. Epub 2002 Jul 13.


Objective: UDP-glucuronosyltransferase (UGT) 2B7 is the major UGT isoform responsible for the 3- and 6-glucuronidation of morphine in humans. Studies in rats have indicated that UGT1A1 may also contribute to the formation of morphine 3-glucuronide (M3G). Our objective was to investigate whether the UGT2B7 H268Y and UGT1A1*28 polymorphisms contribute to the variability in morphine glucuronide-to-morphine plasma ratios among cancer patients undergoing analgesic therapy with morphine.

Methods: Seventy patients with normal hepatic and renal function using slow-release morphine to relieve cancer pain were included. UGT2B7 genotyping was performed using restriction enzyme analysis of polymerase chain reaction (PCR)-amplified DNA fragments. Wild-type and variant alleles of the UGT1A1 gene were identified using sizing of PCR-amplified fragments. Morphine 6-glucuronide (M6G)/morphine, M3G/morphine, and M3G/M6G plasma ratios were compared between genotypes.

Results: The M3G/morphine, M6G/morphine, and M3G/M6G plasma ratios varied 16-, 42-, and sevenfold, respectively, among individuals. No statistically significant differences in plasma ratios were found between individuals possessing UGT2B7 H/H ( n=20), H/Y ( n=30), or Y/Y ( n=20) genotypes. Five patients were homozygous for the UGT1A1 TA(7) allele, which is associated with reduced UGT1A1 gene expression. However, the mean M3G/M6G and M3G/morphine plasma ratios in TA(7) homozygous subjects did not differ significantly from those of heterozygous or homozygous wild-type (TA(6)) individuals.

Conclusion: The UGT2B7 H268Y polymorphism cannot account for the considerable variation in glucuronide-to-morphine ratios in cancer patients. Moreover, the contribution of UGT1A1 to the formation of M3G appears to be of minor biological significance, at least in a UGT2B7 background.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / blood*
  • Analgesics, Opioid / therapeutic use
  • Genotype
  • Glucuronosyltransferase / genetics*
  • Humans
  • Isoenzymes / genetics
  • Middle Aged
  • Morphine / administration & dosage
  • Morphine / blood*
  • Morphine / therapeutic use
  • Morphine Derivatives / blood*
  • Neoplasms / blood*
  • Neoplasms / physiopathology
  • Pain / drug therapy
  • Reverse Transcriptase Polymerase Chain Reaction


  • Analgesics, Opioid
  • Isoenzymes
  • Morphine Derivatives
  • morphine-6-glucuronide
  • Morphine
  • Glucuronosyltransferase
  • morphine-3-glucuronide