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Research Fellow, Department of Medicine, Christchurch School of Medicine, Private Bag 4345, Christchurch, New Zealand fax 64 3 364 1003, sharon.gardiner{at}cdhb.govt.nz
Gastroenterologist, Department of Gastroenterology, Box Hill Hospital, Monash University, Victoria, Australia
Research Fellow, Department of Pathology, Christchurch School of Medicine
Research Fellow, Department of Medicine, Christchurch School of Medicine
Gastroenterologist and Clinical Pharmacologist, Departments of Gastroenterology and Clinical Pharmacology, Christchurch Hospital, Christchurch, New Zealand
Professor of Medicine and Clinical Pharmacologist, Departments of Medicine and Clinical Pharmacology, Christchurch School of Medicine and Christchurch Hospital
Published Online, March 27, 2007. www.theannals.com, DOI 10.1345/aph.1H152a
The authors stated that mercaptopurine, the initial product of azathioprine, was the major active metabolite. This is not the case. It is the thioguanine nucleotides (TGNs) enzymatically produced from mercaptopurine that are thought to be responsible for most of the immunosuppressive effects of these drugs.3 Mercaptopurine itself is regarded as inactive.4 Despite this inaccuracy, failure to detect mercaptopurine (limit of detection 5 µg/L) in the milk of 2 mothers is reassuring and confirms a low infant "dose" of mercaptopurine in milk (<0.1% of the maternal dose, corrected for weight).2
We too have studied the likely safety of azathioprine in breast-feeding,
but elected to focus on infant exposure to the active TGNs. We reasoned that
the TGNs would be unlikely to be detected in milk given that they reside
intracellularly. Therefore, we sampled blood from 6 mother–infant pairs
(n = 45 and n = 2 [unpublished]) for determination of TGN
concentrations during maternal use of azathioprine 1.2–2.1 mg/kg/day.
Thiopurine methyltransferase (TPMT) genotype (a major determinant of TGN
concentrations) and concentrations of the potentially hepatotoxic metabolites
methylmercaptopurine nucleotides (MMPN) were also determined. All mothers and
their infants (
3 mo of age) had the wild-type TPMT genotype, suggesting
that "normal" exposure to the TGNs should be expected. Both TGNs
and MMPNs were below the limit of quantification (30 pmol/8 x
108 red blood cells) in all 6 infants, whereas maternal
concentrations were consistent with therapeutic exposure (234–449 and
284–1342 pmol/8 x 108 red blood cells,
respectively). No adverse effects were detected in any of the 6
infants.5
The consistent findings of both studies, in terms of the undetectable concentrations of the inactive mercaptopurine in milk2 and the active TGN in infant blood,5 are reassuring. The results suggest that azathioprine may be safely used in breast-feeding in mother–infant pairs with the wild-type TPMT genotype. The availability of sensitive assays for TGN concentrations in some centers offers a valuable means of objectively assessing infant exposure during clinical use and could be used in conjunction with other clinical assessments. Clearly, risk–benefit assessment remains essential in all cases. Further study is warranted, especially among mother–infant pairs with intermediate or deficient TPMT genotypes who may achieve greater exposure to mercaptopurine and the active TGN metabolites for a given azathioprine dose.
Footnotes
Comments on articles previously published are submitted to the authors of those articles. When no reply is published, either the author chose not to respond or did not do so in a timely fashion. Comments and replies are not peer reviewed.–ED.
References
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