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


CONCLUSIONS
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.
Holthe
Monica
M
Institute of Cancer Research and Molecular Biology, Faculty of Medicine, Norwegian University of Science and Technology, 7489 Trondheim, Norway.
Klepstad
Pål
P
Zahlsen
Kolbjørn
K
Borchgrevink
Petter C
PC
Hagen
Lars
L
Dale
Ola
O
Kaasa
Stein
S
Krokan
Hans E
HE
Skorpen
Frank
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008875:Middle Aged; D009020:Morphine / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D009022:Morphine Derivatives / Q000097:blood*; D009369:Neoplasms / Q000097:blood* / Q000503:physiopathology; D010146:Pain / Q000188:drug therapy; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000701:Analgesics, Opioid; D007527:Isoenzymes; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D009020:Morphine; D014453:Glucuronosyltransferase; C018108:morphine-3-glucuronide