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 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.
Jiang
Hao
H
Clinical Pharmacology Research Center, Peking Union Medical University Hospital, Beijing, China.
Lu
Jing
J
Jiang
Ji
J
Hu
Pei
P
D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006063:Chorionic Gonadotropin / Q000097:blood; D005260:Female; D005467:Floxuridine / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D031901:Gestational Trophoblastic Disease / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007958:Leukocyte Count; D008657:Metabolic Clearance Rate; D009504:Neutrophils / Q000473:pathology; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011446:Prospective Studies; D014498:Uracil / Q000031:analogs & derivatives* / Q000097:blood*
D000964:Antimetabolites, Antineoplastic; D006063:Chorionic Gonadotropin; D011355:Prodrugs; C007419:dihydrouracil; D005467:Floxuridine; D014498:Uracil; D005472:Fluorouracil