Morphine glucuronide-to-morphine plasma ratios are unaffected by the UGT2B7H268Y and UGT1A1 28polymorphisms in cancer patients on chronic morphine therapy

• Published in: European journal of clinical pharmacology 2002-08, Vol.58 (5), p.353
• Main Authors: Holthe, Monica, Klepstad, Pål, Zahlsen, Kolbjørn, Borchgrevink, Petter C, Hagen, Lars, Dale, Ola, Stein Kaasa, Krokan, Hans E, Skorpen, Frank
• Format: Article
• Language: English
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-002-0490-1

Abstract 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 TA7 allele, which is associated with reduced UGT1A1 gene expression. However, the mean M3G/M6G and M3G/morphine plasma ratios in TA7 homozygous subjects did not differ significantly from those of heterozygous or homozygous wild-type (TA6) 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.