Top

Published in:

01-01-2010 | Original Article

Association of UGT2B7 and ABCB1 genotypes with morphine-induced adverse drug reactions in Japanese patients with cancer

Authors: Ken-ichi Fujita, Yuichi Ando, Wataru Yamamoto, Toshimichi Miya, Hisashi Endo, Yu Sunakawa, Kazuhiro Araki, Keiji Kodama, Fumio Nagashima, Wataru Ichikawa, Masaru Narabayashi, Yuko Akiyama, Kaori Kawara, Mari Shiomi, Hiroyasu Ogata, Hiroyasu Iwasa, Yasushi Okazaki, Takashi Hirose, Yasutsuna Sasaki

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2010

Abstract

Purpose

To investigate the effects of genetic polymorphisms on morphine-induced adverse events in cancer patients.

Methods

We examined the relation of morphine-related adverse events to polymorphisms in UDP-glucuronosyltransferase (UGT) 2B7, ATP-binding cassette, sub-family B, number 1 (ABCB1), and μ-opioid receptor 1 genes in 32 Japanese cancer patients receiving oral controlled-release morphine sulfate tablets.

Results

The T/T genotype at 1236 or TT/TT diplotype at 2677 and 3435 in ABCB1 was associated with significantly lower frequency of fatigue (grades 1–3) (P = 0.012 or 0.011, Fisher’s exact test). The UGT2B7*2 genotype was associated with the frequency of nausea (grades 1–3) (P = 0.023). The frequency of nausea was higher in patients without UGT2B7*2 allele than others. The diplotype at 2677 and 3435 in ABCB1 was associated with the frequency of vomiting (grades 1–3) (P = 0.011). No patient whose diplotype was consisted of no GC allele at 2677 and 3435 suffered from vomiting.

Conclusion

Our findings suggest that pharmacogenetics can be used to predict the risk of morphine-induced adverse events.

Evans WE, Relling MV (1999) Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286:487–491CrossRefPubMed

Evans WE, McLeod HL (2003) Pharmacogenomics—drug disposition, drug targets, and side effects. N Engl J Med 348:538–549CrossRefPubMed

Evans WE, Relling MV (2004) Moving towards individualized medicine with pharmacogenomics. Nature 429:464–468CrossRefPubMed

Huang RS, Ratain MJ (2009) Pharmacogenetics and pharmacogenomics of anticancer agents. CA Cancer J Clin 59:42–55CrossRefPubMed

Coffman BL, Rios GR, King CD et al (1997) Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos 25:1–4PubMed

Christrup LL (1997) Morphine metabolites. Acta Anaesthesiol Scand 41:116–122CrossRefPubMed

Hirota T, Ieiri I, Takane H et al (2003) Sequence variability and candidate gene analysis in two cancer patients with complex clinical outcomes during morphine therapy. Drug Metab Dispos 31:677–680CrossRefPubMed

Duguay Y, Báár C, Skorpen F et al (2004) A novel functional polymorphism in the uridine diphosphate-glucuronosyltransferase 2B7 promoter with significant impact on promoter activity. Clin Pharmacol Ther 75:223–233CrossRefPubMed

Somogyi AA, Barratt DT, Coller JK (2007) Pharmacogenetics of opioids. Clin Pharmacol Ther 81:429–444CrossRefPubMed

10.

Wandel C, Kim R, Wood M et al (2002) Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein. Anesthesiology 96:913–920CrossRefPubMed

11.

Sai K, Itoda M, Saito Y et al (2006) Genetic variations and haplotype structures of the ABCB1 gene in a Japanese population: an expanded haplotype block covering the distal promoter region, and associated ethnic differences. Ann Hum Genet 70:605–622CrossRefPubMed

12.

Campa D, Gioia A, Tomei A et al (2008) Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther 83:559–566CrossRefPubMed

13.

LaForge KS, Yuferov V, Kreek MJ (2000) Opioid receptor and peptide gene polymorphisms: potential implications for addictions. Eur J Pharmacol 410:249–268CrossRefPubMed

14.

Hoehe MR, Köpke K, Wendel B (2000) Sequence variability and candidate gene analysis in complex disease: association of mu opioid receptor gene variation with substance dependence. Hum Mol Genet 9:2895–2908CrossRefPubMed

15.

Zhang Y, Wang D, Johnson AD et al (2005) Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem 280:32618–32624CrossRefPubMed

16.

Klepstad P, Rakvåg TT, Kaasa S et al (2004) The 118A > G polymorphism in the human mu-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand 48:1232–1239CrossRefPubMed

17.

Sai K, Kaniwa N, Itoda M et al (2003) Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan. Pharmacogenetics 13:741–757CrossRefPubMed

18.

Coffman BL, King CD, Rios GR et al (1998) The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268). Drug Metab Dispos 26:73–77PubMed

19.

Meineke I, Freudenthaler S, Hofmann U et al (2002) Pharmacokinetic modelling of morphine, morphine-3-glucuronide and morphine-6-glucuronide in plasma and cerebrospinal fluid of neurosurgical patients after short-term infusion of morphine. Br J Clin Pharmacol 54:592–603CrossRefPubMed

20.

Kim RB, Leake BF, Choo EF et al (2001) Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 70:189–199CrossRefPubMed

21.

Hoffmeyer S, Burk O, von Richter O et al (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 97:3473–3478CrossRefPubMed

22.

Fellay J, Marzolini C, Meaden ER et al (2002) Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet 359:30–36CrossRefPubMed

23.

Nasi M, Borghi V, Pinti M et al (2003) MDR1 C3435T genetic polymorphism does not influence the response to antiretroviral therapy in drug-naive HIV-positive patients. AIDS 17:1696–1698CrossRefPubMed

24.

Saitoh A, Singh KK, Powell CA et al (2005) An MDR1-3435 variant is associated with higher plasma nelfinavir levels and more rapid virologic response in HIV-1 infected children. AIDS 19:371–380CrossRefPubMed

25.

Verstuyft C, Marcellin F, Morand-Joubert L et al (2005) Absence of association between MDR1 genetic polymorphisms, indinavir pharmacokinetics and response to highly active antiretroviral therapy. AIDS 19:2127–2131CrossRefPubMed

26.

Haas DW, Smeaton LM, Shafer RW et al (2005) Pharmacogenetics of long-term responses to antiretroviral regimens containing Efavirenz and/or Nelfinavir: an Adult Aids Clinical Trials Group Study. J Infect Dis 192:1931–1942CrossRefPubMed

27.

Kajinami K, Brousseau ME, Ordovas JM et al (2004) Polymorphisms in the multidrug resistance-1 (MDR1) gene influence the response to atorvastatin treatment in a gender-specific manner. Am J Cardiol 93:1046–1050CrossRefPubMed

28.

Siddiqui A, Kerb R, Weale ME et al (2003) Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med 348:1442–1448CrossRefPubMed

29.

Zheng HX, Webber SA, Zeevi A et al (2004) The impact of pharmacogenomic factors on steroid dependency in pediatric heart transplant patients using logistic regression analysis. Pediatr Transplant 8:551–557CrossRefPubMed

30.

Yi SY, Hong KS, Lim HS et al (2004) A variant 2677A allele of the MDR1 gene affects fexofenadine disposition. Clin Pharmacol Ther 76:418–427CrossRefPubMed

31.

Morita N, Yasumori T, Nakayama K (2003) Human MDR1 polymorphism: G2677T/A and C3435T have no effect on MDR1 transport activities. Biochem Pharmacol 65:1843–1852PubMed

32.

Kimchi-Sarfaty C, Gribar JJ, Gottesman MM (2002) Functional characterization of coding polymorphisms in the human MDR1 gene using a vaccinia virus expression system. Mol Pharmacol 62:1–6CrossRefPubMed

33.

Coulbault L, Beaussier M, Verstuyft C et al (2006) Environmental and genetic factors associated with morphine response in the postoperative period. Clin Pharmacol Ther 79:316–324CrossRefPubMed

34.

Reyes-Gibby CC, Shete S, Rakvåg T et al (2007) Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain 130:25–30CrossRefPubMed

Title: Association of UGT2B7 and ABCB1 genotypes with morphine-induced adverse drug reactions in Japanese patients with cancer
Authors: Ken-ichi Fujita
Yuichi Ando
Wataru Yamamoto
Toshimichi Miya
Hisashi Endo
Yu Sunakawa
Kazuhiro Araki
Keiji Kodama
Fumio Nagashima
Wataru Ichikawa
Masaru Narabayashi
Yuko Akiyama
Kaori Kawara
Mari Shiomi
Hiroyasu Ogata
Hiroyasu Iwasa
Yasushi Okazaki
Takashi Hirose
Yasutsuna Sasaki
Publication date: 01-01-2010
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2010
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-009-1029-2

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 2/2010

A randomized comparative study of high-dose and low-dose hepatic arterial infusion chemotherapy for intractable, advanced hepatocellular carcinoma

A phase I/II trial of GW572016 (lapatinib) in recurrent glioblastoma multiforme: clinical outcomes, pharmacokinetics and molecular correlation

A phase I trial of UCN-01 and prednisone in patients with refractory solid tumors and lymphomas

A phase I study of larotaxel (XRP9881) administered in combination with carboplatin in chemotherapy-naïve patients with stage IIIB or stage IV non-small cell lung cancer

Phase II study of fixed dose rate gemcitabine as radiosensitizer for newly diagnosed glioblastoma multiforme

Preclinical rationale for combined use of endocrine therapy and 5-fluorouracil but neither doxorubicin nor paclitaxel in the treatment of endocrine-responsive breast cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer