Faculty Collaboration Database

Split-dose administration of thiopurine drugs: a novel and effective strategy for managing preferential 6-MMP metabolism. Aliment Pharmacol Ther 2012 Sep;36(5):449-58

Date

07/13/2012

Pubmed ID

22784257

DOI

10.1111/j.1365-2036.2012.05206.x

Scopus ID

2-s2.0-84864680763 (requires institutional sign-in at Scopus site)   69 Citations

Abstract

BACKGROUND: Mercaptopurine and azathioprine (AZA) are efficacious in treating IBD. 6-tioguanine (6-TGN) levels correlate with therapeutic efficacy, whereas high 6-methylmercaptopurine (6-MMP) levels are associated with hepatotoxicity and myelotoxicity. Some IBD patients exhibit dose-limiting preferential 6-MMP production, which may lead to undesired side effects and impact efficacy.

AIM: To review the outcomes of thiopurine split-dosing in patients with preferential 6-MMP metabolism.

METHODS: A retrospective chart review of 179 IBD patients treated at the Cedars-Sinai IBD Center with AZA or mercaptopurine was performed. Preferential 6-MMP metabolisers with 6-MMP levels greater than 7000 pmol/8 × 10(8) erythrocytes who underwent split-dosing were identified and assessed for biochemical and clinical responses to these dose modifications.

RESULTS: A total of 20 of 179 patients met the criteria for preferential 6-MMP metabolism and underwent thiopurine split-dosing. Dividing the total daily thiopurine dose led to a reduction in 6-MMP levels (11785 vs. 5324 pmol/8 × 10(8) erythrocytes; P < 0.0001) without negatively affecting clinical disease activity or 6-TGN levels (239 vs. 216 pmol/8 × 10(8) erythrocytes; P = N.S.) and led to resolution of 6-MMP associated side effects (elevated transaminases, leucopenia and flu-like symptoms) in all but two patients. After mean follow-up of 36 months, 12 patients remained in clinical remission on split-dose mercaptopurine. Five of the remaining eight patients escalated to anti-TNF therapy, two progressed to surgery, and one switched to tioguanine therapy.

CONCLUSION: Split-dose administration of mercaptopurine/AZA represents an alternative option in IBD patients with preferential 6-MMP metabolism who might otherwise require steroid exposure or escalation of therapy.

Author List

Shih DQ, Nguyen M, Zheng L, Ibanez P, Mei L, Kwan LY, Bradford K, Ting C, Targan SR, Vasiliauskas EA

Author

Ling Mei MD Associate Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Azathioprine
Dose-Response Relationship, Drug
Erythrocytes
Female
Humans
Immunosuppressive Agents
Inflammatory Bowel Diseases
Male
Mercaptopurine
Middle Aged
Retrospective Studies
Treatment Outcome
Young Adult