Important role of the dihydrouracil/uracil ratio in marked interpatient variations of fluoropyrimidine pharmacokinetics and pharmacodynamics

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 with5-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/(beta-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/beta-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.