Uridine glucuronosyltransferase 2B7 polymorphisms and epirubicin pharmacokinetics

13071 Background: Epirubicin (epi) is a widely used anthracycline for the treatment of breast cancer. In contrast to its optical isomer doxorubicin, epi is predominantly glucuronidated by uridine glucuronosyltransferase 2B7 (UGT2B7). UGT2B7 has a T to C polymorphism at position -161 in the enhancer region which correlated with efficacy of morphine glucuronidation (Sawyer et al. Clin Pharmcol Ther 2003). Methods: We performed a prospective pharmacogenetic study of FEC100 (5-fluorouracil 500 mg/m2, Epi 100 mg/m2 and cyclophosphamide 500 mg/m2) given every 3 wks in early stage breast cancer pts. Drug levels were drawn at 1 and 24 hrs. We have determined levels of epi, epi-glucuronide (epiG), epirubicinol (epiol), and epiol-glucuronide (epiolG) in 78 of the 120 pts. The levels of epi and its metabolites were measured using an HPLC with fluorescence detection using the method of Fogli et al with modifications. Patient characteristics-median (range): age 50 (28 - 67), sex 77 F/ 1 M, baseline AST 22 U/L (13–66), ALT 20 U/L (5–90), bilirubin 7 umol/L (2–24), creatinine 73 umol/L (51–126). Results: 14 pts were TT homozygotes, 45 were CT heterozygotes, and 19 were CC homozygotes. Concentrations (ng/ml, median (range)) of epi, epiG, epiol, and epiolG at 1 hr respectively were 91 (39–481), 280 (0–981) 76 (14–212) 76 (0–276). There was no relationship between epiG concentration and genotype: 315 (median) TT, 263 CT, 288 CC. Patients with a TT genotype had a lower epiol concentrations (median, ng/ml) at 24 hr: 12 TT, 23 CT, 25 CC; p = 0.04. Conclusions: This analysis shows a relationship between UGT2B7 genotype and epi pharmacokinetics. We are completing analysis of all 120 samples and plan to perform a formal NONMEM analysis. No significant financial relationships to disclose.