Authors: Wong, D. R.¹; den Dulk, M. O.²; Derijks, L. J. J.³; Gemmeke, E. H. K. M.⁴; Hooymans, P. M.¹

Source: British Journal of Clinical Pharmacology, Volume 63, Number 4, April 2007 , pp. 508-508(1)

Publisher: Wiley-Blackwell

Abstract:

Introduction: 

Azathioprine (AZA) is a thiopurine prodrug clinically used for immunosuppression in the treatment of auto-immune inflammatory diseases and in regimens of organ transplantations. The pharmacological action of AZA is based on the formation of 6-mercaptopurine (6-MP), which is metabolised into a variety of active thiopurine-nucleotide metabolites. We report the case of a 55 year old woman (bodyweight 30 kg) with chronic pancreatitis, weight loss, and progressive elevation of liver transaminases and serum amylase. Case description: 

The woman was treated with prednisolone (30 mg 1 dd; tapered 5 mg each week) and AZA (75 mg 1 dd; 5 weeks later 150 mg 1 dd). Despite good patient-compliance verified during hospital-stay, none of the active metabolites of AZA, 6-thioguanine-nucleotides (6TGN) and 6-methylmercaptopurine ribonucleotides (6MMPR), were detected in erythrocytes. After two months of treatment clinical improvement was achieved, but no normalisation of laboratory parameters. Subsequently, AZA was switched to 6-MP 75 mg 1 dd, and allopurinol 100 mg 1 dd was added. After one week the 6TGN level was 616 pmol/ 8 × 10⁸ red blood cells (RBC), the 6MMPR level was 1319 pmol/ 8 × 10⁸ RBC.

Two weeks later the 6TGN level was 1163 pmol/ 8 × 10⁸ RBC and the 6MMPR level 10015 pmol/ 8 × 10⁸ RBC.

These 6TGN and 6MMPR levels were higher than the upper limits of the therapeutic ranges (500 pmol/ 8 × 10⁸ RBC and 5700 pmol/ 8 × 10⁸ RBC, respectively). Therefore, treatment with 6-MP was discontinued. A week later the 6TGN and 6MMPR levels decreased to 686 pmol/ 8 × 10⁸ RBC and 4027 pmol/ 8 × 10⁸ RBC, respectively.

Genotyping of the enzym thiopurine S-methyl transferase (TPMT) revealed a wild-type TPMT (*1/*1) genotype. Discussion: 

To our knowledge this is the first report of a patient who was not able to form detectable active thiopurine metabolites on the treatment with AZA.

AZA is normally rapidly and almost completely converted to 6-MP and methylnitroimidazole in the liver. 6-MP is then further catabolised by xanthine-oxidase (XO) and TPMT or anabolised by hypoxanthine phosphoribosyl transferase (HPRT). Remarkably, treatment with 6-MP in combination with the XO-inhibitor allopurinol resulted in a myelotoxic 6TGN level in the first week after start of treatment.

There are two hypotheses on the mechanism by which this finding could be explained. First, an `ultra-high' XO activity results in a direct and complete conversion of 6-MP into 6-thiouric acid. Secondly, AZA is not converted into 6-MP. Consequently, there is no formation of active thiopurine nucleotides out of 6-MP.

Also, a combination of these two mechanisms could lead to a decreased formation of active thiopurine metabolites. Conclusion: 

Our finding indicates non-conventional insights in the biotransformation of AZA contributing to an interindividual variation in thiopurine metabolism.

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1365-2125.2007.02886_10.x

Affiliations: 1: Department of Clinical Pharmacy, Maasland Hospital, Sittard; 2: Department of Internal Medicine, St. Jans Gasthuis Hospital, Weert; 3: Department of Clinical Pharmacy, Maxima Medical Centre, Veldhoven; 4: Department of Clinical Pharmacy, St. Jans Gasthuis Hospital, Weert; The Netherlands

Publication date: 2007-04-01

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