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

Abstract

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/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.

The Uracil Breath Test in the Assessment of Dihydropyrimidine Dehydrogenase Activity: Pharmacokinetic Relationship between Expired 13CO2 and Plasma [2-13C]Dihydrouracil

“…The concentration of cytosolic protein was quantified by the Bradford method (13). A reaction mixture containing 250 Ag cytosolic protein, NADPH, buffer A, and [6][7][8][9][10][11][12][13][14] C]-5-FU was incubated for 30 minutes. Every 5 minutes, 130 AL aliquots were removed and added to an equal volume of ice-cold ethanol.…”

“…Specifically, 5-FU dose optimization may be based on the plasma DUUR observed before 5-FU administration (6). Jiang et al have also showed that the pre-5-FU treatment DUUR may be a good index of DPD activity (7,8).Our laboratory recently reported the rapid noninvasive phenotypic [2-13 C]uracil breath test (UraBT) for assessment of DPD activity with 96% specificity and 100% sensitivity (9). Application of the UraBT to a large population of cancer-free subjects (n = 255) showed an observed 86% sensitivity (with 12 of 14 DPD-deficient subjects identified as DPD deficient) and…”

“…Specifically, 5-FU dose optimization may be based on the plasma DUUR observed before 5-FU administration (6). Jiang et al have also showed that the pre-5-FU treatment DUUR may be a good index of DPD activity (7,8).…”

“…Linear regression analysis was used to calculate the equation of the line and determine the formation rate of [6][7][8][9][10][11][12][13][14] C]-5-FUH 2 . DPD enzyme activity was calculated by dividing the formation rate of [6][7][8][9][10][11][12][13][14] C]-5-FUH 2 by the amount of protein used in the reaction mixture (i.e., nmol/min/ mg protein). Subjects were considered to be partially DPD deficient by radioassay when their fresh PBMC DPD activity was <0.18 nmol/min/ mg protein (11).…”

“…The UraBT principle and detailed methodology has been described previously (9). At f8 a.m. on the day of testing, fasting subjects were weighed and an aqueous solution containing 6 mg/kg [2][3][4][5][6][7][8][9][10][11][12][13] C]uracil (Cambridge Isotope Laboratories, Inc., Andover, MA) was prepared. Subjects donated three baseline breath samples into 1.2 L breath bags (Otsuka Pharmaceutical, Tokushima, Japan) followed by oral administration of the [2][3][4][5][6][7][8][9][10][11][12][13] C]uracil solution.…”