Determination of Mercaptopurine metabolites and toxicity in children

Acute Lymphocytic Leukemia is a widespread disease, mostly affecting childhood.The introduction of 6-mercaptopurine (6-MP), an antimetabolite drug, begins in the consolidation phase, and forms the backbone of remission therapy. 6-MP is a pro-drug, and requires activation to 6-TGNs which are false nucleotides incorporated into DNA, however, a competing pathway led by TPMT enzyme results in 6-MMP production, which was reported to have a hepatotoxic effect. A genetic polymorphism of TPMT could result in myelosuppression upon administration of standard drug doses, and dose reduction based on the enzyme's genotype is done empirically, with no individualization. A robust, sensitive HPLC method for the quantitation of 6-TGNs and 6-MMP was developed via a Design of Experiment approach to relate levels of these metabolites with emergence of signs of toxicity, paving the road to accurate dose calculations and thus providing a cost effective treatment approach. A strong correlation was manifested between levels of the metabolites with RBCs, WBCs, and ALT,AST enzymes. The book is of interest to clinical pharmacy staff in children cancer hospitals and biomedical analysts in general.