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UGT1A1 polymorphism and hyperbilirubinemia in a patient who received sorafenib

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Abstract

Purpose

To report a single case of uridine glucuronosyltransferase 1A1 (UGT1A1) polymorphism and hyperbilirubinemia in a patient who received sorafenib.

Methods

A 63-year-old man with cirrhosis was diagnosed with hepatocellular carcinoma. His cirrhosis was categorized as Child-Pugh A, total bilirubin concentration was 24 μmol/L (normal range <20 μmol/L). The patient was enrolled in a phase I trial combination study of cyclophosphamide and doxorubicin combined with sorafenib.

Results

After a single infusion of doxorubicin and cyclophosphamide and 7 days of sorafenib, he presented with an elevated bilirubin concentration (48 μmol/L). Unconjugated bilirubin was 38 μmol/L and conjugated was 10 μmol/L. The patient was found to have one mutant allele (UGT1A1*28).

Conclusions

The isolated increase in serum bilirubin levels in our patient was probably due to sorafenib-induced UGT1A1 inhibition that manifested itself due both to the patient having one UGT1A1*28 allele and the presence of underlying liver disease. Bilirubin elevations in patients treated with sorafenib could indicate progression or drug toxicity; hence, these possibilities need to be ruled out. We would suggest that when patients develop hyperbilirubinemia while taking sorafenib for any indication, consideration be given to obtaining a fractionation of bilirubin and consideration of UGT1A1 genotyping in order to exclude a Gilbert’s syndrome as possible reason for the hyperbilrubinemia. Further studies are warranted to analyze the impact of sorafenib treatment on unconjugated bilirubin blood levels in patients with Gilbert’s syndrome.

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References

  1. Cheng A, Kang Y, Chen Z et al (2008) Randomized phase III trial of sorafenib versus placebo in Asian patients with advanced hepatocellular carcinoma. J Clin Oncol 26(15s):a4509

    Google Scholar 

  2. Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390

    Article  PubMed  CAS  Google Scholar 

  3. Strumberg D, Clark JW, Awada A et al (2007) Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. Oncologist 12:426–437

    Article  PubMed  CAS  Google Scholar 

  4. Monaghan G, Ryan M, Seddon R, Hume R, Burchell B (1996) Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert’s syndrome. Lancet 347:578–581

    Article  PubMed  CAS  Google Scholar 

  5. Wells PG, Mackenzie PI, Chowdhury JR et al (2004) Glucuronidation and the UDP-glucuronosyltransferases in health and disease. Drug Metab Dispos 32:281–290

    Article  PubMed  CAS  Google Scholar 

  6. Bosch TM, Meijerman I, Beijnen JH (2006) Genetic polymorphisms of drug-metabolising enzymes and drug transporters in the chemotherapeutic treatment of cancer. Clin Pharmacokinet 45:253–285

    Article  PubMed  CAS  Google Scholar 

  7. Strassburg CP (2008) Pharmacogenetics of Gilbert’s syndrome. Pharmacogenomics 9:703–715

    Article  PubMed  CAS  Google Scholar 

  8. Rudenski AS, Halsall DJ (1998) Genetic testing for Gilbert’s syndrome: how useful is it in determining the cause of jaundice? Clin Chem 44(8 Pt 1):1604–1609

    PubMed  CAS  Google Scholar 

  9. Hirschfield GM, Alexander GJ (2006) Gilbert’s syndrome: an overview for clinical biochemists. Ann Clin Biochem 43(Pt 5):340–343

    Article  PubMed  CAS  Google Scholar 

  10. Burchell B, Hume R (1999) Molecular genetic basis of Gilbert’s syndrome. J Gastroenterol Hepatol 14:960–966

    Article  PubMed  CAS  Google Scholar 

  11. Biason P, Masier S, Toffoli G (2008) UGT1A1*28 and other UGT1A polymorphisms as determinants of irinotecan toxicity. J Chemother 20:18–65

    Google Scholar 

  12. Wen Z, Tallman MN, Ali SY et al (2007) UDP-glucuronosyltransferase 1A1 is the principal enzyme responsible for etoposide glucuronidation in human liver and intestinal microsomes: structural characterization of phenolic and alcoholic glucuronides of etoposide and estimation of enzyme kinetics. Drug Metab Dispos 35:371–380

    Article  PubMed  CAS  Google Scholar 

  13. Lathia C, Lettieri J, Cihon F et al (2006) Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics. Cancer Chemother Pharmacol 57:685–692

    Article  PubMed  CAS  Google Scholar 

  14. Wilhelm S, Chien DS (2002) BAY 43–9006: preclinical data. Curr Pharm Des 8:2255–2257

    Article  PubMed  CAS  Google Scholar 

  15. Bayer NEXAVAR® product monograph. Toronto, Ontario, Bayer Inc, 2007

  16. Abou-Alfa GK, Amadori D, Santoro A et al (2008) Is sorafenib (S) safe and effective in patients (pts) with hepatocellular carcinoma (HCC) and Child-Pugh B (CPB) cirrhosis? J Clin Oncol 26(15S):a4518

    Google Scholar 

  17. Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134

    Article  PubMed  CAS  Google Scholar 

  18. Ratain MJ, Eisen T, Stadler WM et al (2006) Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 24:2505–2512

    Article  PubMed  CAS  Google Scholar 

  19. Merkel C, Marin R, Angeli P et al (2004) A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis. Gastroenterology 127:476–484

    Article  PubMed  CAS  Google Scholar 

  20. Goldstein LJ, O’Neill A, Sparano JA et al (2008) Concurrent doxorubicin plus docetaxel is not more effective than concurrent doxorubicin plus cyclophosphamide in operable breast cancer with 0 to 3 positive axillary nodes: North American Breast Cancer Intergroup Trial E 2197. J Clin Oncol 26:4092–4099

    Article  PubMed  CAS  Google Scholar 

  21. Hutchins LF, Green SJ, Ravdin PM et al (2005) Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol 23:8313–8321

    Article  PubMed  CAS  Google Scholar 

  22. Katsumata N, Watanabe T, Minami H et al (2009) Phase III trial of doxorubicin plus cyclophosphamide (AC), docetaxel, and alternating AC and docetaxel as front-line chemotherapy for metastatic breast cancer: Japan Clinical Oncology Group trial. Ann Oncol (Advance Access published March 2)

  23. Liu MC, Demetri GD, Berry DA et al (2008) Cancer and Leukemia Group B. Dose-escalation of filgrastim does not improve efficacy: clinical tolerability and long-term follow-up on CALGB study 9141 adjuvant chemotherapy for node-positive breast cancer patients using dose-intensified doxorubicin plus cyclophosphamide followed by paclitaxel. Cancer Treat Rev 34:223–230

    Article  PubMed  CAS  Google Scholar 

  24. Rastogi P, Anderson SJ, Bear HD et al (2008) Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 26:778–785

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada

    Judith Meza-Junco, Quincy S.-C. Chu, Ruslan Stefanyschyn & Michael B. Sawyer

  2. Bayer Healthcare Pharmaceuticals Inc, P.O. Box 1000, Montville, NJ, 07045-1000, USA

    Olaf Christensen & Prabhu Rajagopalan

  3. Department of Human Genetics, University of Chicago, 5841 South Maryland Avenue, Room L035/MC0077, Chicago, IL, 60637, USA

    Soma Das

Authors
  1. Judith Meza-Junco
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  2. Quincy S.-C. Chu
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  3. Olaf Christensen
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  4. Prabhu Rajagopalan
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  5. Soma Das
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  6. Ruslan Stefanyschyn
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  7. Michael B. Sawyer
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Correspondence to Judith Meza-Junco.

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Meza-Junco, J., Chu, Q.SC., Christensen, O. et al. UGT1A1 polymorphism and hyperbilirubinemia in a patient who received sorafenib. Cancer Chemother Pharmacol 65, 1–4 (2009). https://doi.org/10.1007/s00280-009-1096-4

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  • DOI: https://doi.org/10.1007/s00280-009-1096-4

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