Correlation of Genetic Polymorphism of Azathioprine Metabolizing Enzymes and Correlation to Clinical Adverse Effects

Correlation of Genetic Polymorphism of Two Azathioprine Metabolizing Enzymes and Their Correlation to Clinical Adverse Effects

Azathioprine (AZA) has long been used in dermatology in treating autoimmune bullous dermatoses and generalized eczematous disorders as well as some photodermatoses. Its metabolic process inside human body and its side effects relies on genetic polymorphism of some enzymes such as thiopurine s-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase gene (ITPA). This study aims to analyze the relative contribution of TMPT and ITPA mutations to the development of toxicity induced by AZA treatment and to detect the correlation of the genetic polymorphism.

Study Overview

• Status: Completed
• Conditions: Genetic Polymorphism; Azathioprine; Thiopurine Methyltransferase; Inosine Triphosphate Pyrophosphatase
• Intervention / Treatment: Drug: Azathioprine

Detailed Description

Dermatologists have been using azathioprine for more than 30 years. This synthetic purine analog is derived from 6-mercaptopurine. It is thought to act by disrupting nucleic acid synthesis and has recently been found to interfere with T-cell activation. The most recognized uses of azathioprine in dermatology are for immunobullous diseases, generalized eczematous disorders, and photodermatoses. Azathioprine is extensively metabolized, and only about 2% is excreted, unchanged, in the urine. Once freed of its imidazole derivative, the mercaptopurine moiety undergoes metabolism from 3 competing enzymes. Activity of the 2 catabolic enzymes thiopurine s-methyltransferase (TPMT), an enzyme with great genetic polymorphism, and xanthine oxidase (XO) produces inactive metabolites. Decreased TPMT or XO activity results in the increased production of toxic metabolites. Decreased TPMT activity is frequently a consequence of genetic polymorphisms, while decreased XO activity may be mediated by medications such as allopurinol.

Azathioprine is generally well tolerated and has a favorable therapeutic index compared with many other traditional immunosuppressants. Dose-limiting toxicity from azathioprine treatment affects up to 37% of patients. Administration of azathioprine to a patient with TPMT deficiency results in significant accumulation of thioguanine nucleotides, and it becomes clinically manifest by increased hematopoietic toxicity, with potentially grave consequences. Screening for thiopurine methyltransferase (TPMT) polymorphisms, TPMT*3A, *3C, *2 will prospectively identify approximately 10% of patients. In Chinese, the reported incidence of homozygous wild-type、heterozygote、homozygous mutation of TPMT is 95.3%, 4.7% and 0% respectively. The relationship to hematologic complication is more established, but its relationship to gastrointestinal side effects is controversial. Genetic polymorphism of the other newly identified enzyme, inosine triphosphate pyrophosphatase gene (ITPA) has also been associated with other adverse effect of azathioprine, such as flu-like symptoms, rash and pancreatitis. ITPA 94C>A allele is found at low frequency in Central/South American populations (1-2%), at a constant frequency across Caucasian and African populations (6-7%), and is highest in Asian populations (14-19%).

The aim of our study was to determine the relative contribution of, TMPT(A719G) and ITPA(C94A) mutations to the development of toxicity induced by AZA treatment in dermatology patients and to detect the correlation of these two genetic polymorphism.

Hepatotoxicity was defined by serum alanine transaminase levels greater than twice the upper normal limit (50 IU/l) and resolution after withdrawal of AZA; pancreatitis by severe abdominal pain and serum amylase > 800 IU/l; neutropenia by a neutrophil count of < 2.0 × 109 cells.

• Study Type: Observational
• Enrollment (Actual): 166

Contacts and Locations

Study Locations

• Taiwan
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Chinese Han patients

Description

Inclusion Criteria:

• Patients who have used or are using azathioprine in treating skin diseases will be asked about treatment effects and adverse events.

Exclusion Criteria:

• No special exclusion criteria

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genetic polymorphism tests before azathioprine therapy may reduce toxicity	current treatment to nausea/vomiting adverse effects induced by azathioprine combined with pre-therapeutic genetic screening, especially polymorphism ITPA C94A, may reduce the possibility for developing hematopoietic toxicity and/or hepatotoxicity.	2008.1.1

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital

Study record dates

Study Major Dates

• Study Start: February 1, 2007
• Primary Completion (ACTUAL): December 1, 2007
• Study Completion (ACTUAL): January 1, 2008

Study Registration Dates

• First Submitted: September 3, 2007
• First Submitted That Met QC Criteria: September 3, 2007
• First Posted (ESTIMATE): September 5, 2007

Study Record Updates

• Last Update Posted (ESTIMATE): May 17, 2012
• Last Update Submitted That Met QC Criteria: May 16, 2012
• Last Verified: January 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Azathioprine
• Other Study ID Numbers: 200701077M