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PHARMACOGENETICS |
From the Clinical Pharmacology Research Core, National Cancer Institute, Bethesda, Maryland (Dr. Paoluzzi, Dr. Figg, Dr. Sparreboom); Division of Medical Oncology, Regina Elena Cancer Institute, Rome, Italy (Dr. Paoluzzi); Howard Hughes Medical Institute, Bethesda, Maryland (Mr. Singh); Molecular Pharmacology Section, National Cancer Institute, Bethesda, Maryland (Mr. Singh, Dr. Price); Department of Oncology, University of Pisa, Pisa, Italy (Dr. Danesi); and Erasmus MC—Daniel den Hoed Cancer Center, Rotterdam, the Netherlands (Dr. Mathijssen, Dr. Verweij). Dr. Paoluzzi and Mr. Singh contributed equally to this work. Dr. Figg is a member of the American College of Clinical Pharmacology (FCP). Mr. Singh is a Howard Hughes Medical Institute-National Institutes of Health Research Scholar.
The uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A9 isoforms are involved in the phase II biotransformation of the irinotecan metabolite, SN-38. Recently, several variants in the UGT1A1 and UGT1A9 genes have been described with altered functionality in vitro. The aim of this study was to evaluate the functional consequence of the UGT1A1(TA)7TAA (UGT1A1*28), UGT1A9 766G>A (D256N; UGT1A9*5), and UGT1A9 98T>C (M33T; UGT1A9*3) variants in Caucasian patients treated with irinotecan. Pharmacokinetic studies were performed after the first course of irinotecan in 47 males and 47 females. The mean (SD) area under the curves (AUCs) of irinotecan and SN-38 were 20,348 ± 6466 ng•h/mL and 629 ± 370 ng•h/mL, respectively, which is in line with earlier findings. For UGT1A9*5,novariant alleles were observed, whereas for UGT1A9*3, 1 patient with the variant allele was found (allele frequency, 0.633%). The distribution of the UGT1A1*28 variant showed 44 wild-type patients (Wt), 37 heterozygotes (Het), and 5 homozygotes (Var). The median AUC ratio of SN-38G to SN-38 was significantly reduced in carriers of the variant UGT1A1*28 allele (7.00 [Wt] vs. 6.26 [Het] vs. 2.51 [Var]; p = .022). It is concluded that UGT1A9 functional variants are rare in Caucasians and likely to be clinically insignificant in irinotecan regimens. Screening for the UGT1A1*28 polymorphism may identify patients with altered SN-38 pharmacokinetics.
Key Words: UGT1A1 • UGT1A9 • irinotecan • pharmacokinetics • genetic variants • SN-38
Address for reprints: William D. Figg, PharmD, Clinical Pharmacology Research Core, National Cancer Institute, Building 10, Room 5A01, MSC 1910, 9000 Rockville Pike, Bethesda, MD 20892.
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