Pharmacogenomics of Deferiprone Metabolism.

Individuals with transfusion-dependent β-thalassemia can be affected by iron accumulation in the heart and liver, resulting in liver fibrosis, cardiomyopathy and eventual death. As a result, iron chelation treatment is a necessary concurrent therapy for many patients. Deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one) is currently the only orally active iron chelator approved outside the U.S. for the treatment of iron overload. Despite the efficacy of deferiprone in reducing serum ferritin levels and total body iron burden, not all patients respond to the drug, and serious adverse events can require discontinuation of therapy. The variability in drug response, combined with a high rate of side effects, indicate that there may be genetic factors that influence how the drug is metabolized. We have identified the uridine diphosphate glucuronosyltransferase (UGT) enzyme that metabolizes deferiprone. Utilizing human liver microsomes and insect cell supersomes, we have screened UGT 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15 and 2B17 enzymes for deferiprone glucuronidation. Deferiprone glucuronide was detected solely with UGT1A6. Previous reports of linkage disequilibrium between the UGT1A1*28 and UGT1A6*2 alleles (Kohle et. al., 2003; Peters et. al., 2003), combined with the association of the UGT1A1*28 allele with an increased risk of hyperbilirubinemia and gallstone formation in the hemoglobinopathies (Haverfield et. al., 2005), substantiate the importance of elucidating the pharmacogenomics of deferiprone metabolism. From this preliminary data, it will be possible to examine UGT1A6 genetic variation that may contribute to differences in drug efficacy and toxicity, and further delineate any additional enzymes involved in deferiprone metabolism.