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Important Role of the Dihydrouracil/Uracil Ratio in Marked Interpatient Variations of Fluoropyrimidine Pharmacokinetics and Pharmacodynamics

From the Clinical Pharmacology Research Center, Peking Union Medical University Hospital, Beijing, China (Dr H Jiang, Dr J Jiang, Dr Hu) and the Department of Anatomy and Cell Biology, Temple University, Philadelphia, Pennsylvania (Dr Lu).

Dihydropyrimidine dehydrogenase (DPD) deficiency in patients causes severe toxicities in 5-fluorouracil/floxuridine (5-FU/FUDR) treatments. To determine the plasma dihydrouracil/uracil ratio (DUUR) as a potential index for setting 5-FU/FUDR doses, the authors conducted a prospective study on the relationships of the DUUR with 5-FU/FUDR pharmacokinetic and pharmacodynamic parameters. Forty gestational trophoblastic tumor (GTT) patients were treated with 30 mg/kg of 5-FU or prodrug FUDR during a 10-day cycle. The pretreatment DUURs of the patients were determined prior to the treatments, and plasma 5-FU and FUDR concentrations on day 1 of the test cycle were measured to calculate the corresponding pharmacokinetic parameters. The absolute neutrophil count (ANC) and human chorionic gonadotrophins (HCG/ß-HCG) were recorded as the efficacy indexes. The correlation of the DUUR with pharmacokinetic parameters and efficacy indexes was analyzed to look for a relationship between individual doses (in milligrams) and the varied DUUR. Pretreatment DUUR was significantly correlated with the corresponding plasma AUC (r > 0.80, P < .01), the plasma drug clearance (r > 0.78, P < .01), the ANC (r > 0.76, P < 0.01), and the decrease of HCG/ß-HCG levels (r > 0.5, P < 0.01). In addition, the charts for setting 5-FU/FUDR doses were designed for further validation in clinical trials. These findings indicate the important roles of the DUUR in remarkable interpatient variations of fluoropyrimidine pharmacokinetics and pharmacodynamics and propose a better index for setting individual 5-FU/FUDR doses based on interpatient variations in DPD levels.

Key Words: Dihydrouracil/uracil ratio • gestational trophoblastic tumor • 5-fluorouracil • floxuridine • individual dose adjustment

Address for reprints: Hao Jiang, Department of Pharmacology, University of Pennsylvania School of Medicine, 135 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104.

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