A pharmacogenetic study of irinotecan: Genetic polymorphisms in the coding region of UGT1A1 gene and SN-38 glucuronidation in the body

Abstract

13078 Background: Pharmacogenetic testing of UGT1A1*28, a promoter variant of UGT1A1 gene, for estimating a risk of irinotecan toxicity has been introduced into clinical practice. Purpose: To elucidate clinical significance of UGT1A1*6 and UGT1A1*27, the variants in exon 1 that are found mostly in Asians. Methods: Pharmacogenetic relationships were explored between the genotyping results and ratio of area under the concentration-time curve (AUC) of SN-38 and its glucuronide (SN-38G) as a surrogate for a UGT1A1 activity (AUCSN-38/AUCSN-38G) in 36 Japanese patients who received various regimens of irinotecan chemotherapy at doses from 50 to 180 mg/m2. Results: No patients were homozygous for UGT1A1*28 and none had UGT1A1*27. One was heterozygous for UGT1A1*28. Two were homozygous and ten heterozygous for UGT1A1*6, all of whom were wild type with respect to UGT1A1*28. Two patients were simultaneously heterozygous for UGT1A1*28 and UGT1A1*6 that existed on the different chromosomes. The remaining 21 patients did not have any variants studied. The 2 patients who was simultaneously heterozygous for UGT1A1*28 and UGT1A1*6 and the 2 patients who were homozygous for UGT1A1*6 had significantly higher AUCSN-38/AUCSN-38G than the others (P = 0.004). Conclusions: Concurrence of the two UGT1A1 variants, UGT1A1*28 and UGT1A1*6 even in their heterozygous statuses, remarkably altered drug disposition of irinotecan and could enhance susceptibility to the drug. Patients who are homozygous for UGT1A1*6 should also be monitored cautiously. Genotyping of UGT1A1 polymorphisms in the coding region together with UGT1A1*28 is necessary for predicting irinotecan toxicity at least for Asian patient population. [Table: see text] [Table: see text]