Estimation of the effect of food on the disposition of oral 5-fluorouracil in combination with eniluracil.
OBJECTIVE
To determine the effect of food on the pharmacokinetics of 5-fluoruracil (5-FU) taken orally with eniluracil and to compare the performance of different pharmacokinetic analysis methods in the detection a potential food-drug interaction.


METHODS
In a randomized, open-label, two-way crossover study, 12 patients received eniluracil (50 mg, orally) on days 1 and 2 and 5-FU (20 mg/m(2), orally) on day 2 following either a 2-h fast or 20 min after a standard meal. Treatments were separated by 7 days. Timed blood samples were collected during the first two treatment periods and 5-FU concentrations determined by GC/MS. Data were analyzed and pharmacokinetic parameter estimates were obtained using a noncompartmental, two-stage and population analysis methods.


RESULTS
In fasted individuals, the clearance/bioavailability of 5-FU was estimated to be 5.6 l/h. The mean absorption lag-time was 0.24 h and was followed by rapid absorption of 5-FU. Administration of 5-FU and eniluracil with food resulted in a decrease in the 5-FU absorption rate constant by 90%. As a result, the peak plasma concentration (C(max)) of 5-FU was decreased by 21% and the time to C(max) was increased 2.9-fold. Clearance of 5-FU, relative bioavailability, and area under the plasma concentration vs time curve (AUC) remained unchanged with coadministration of food. Similar results were obtained using all three data analysis methods.


CONCLUSIONS
Administration of food with oral 5-FU and eniluracil slowed absorption of 5-FU and decreased 5-FU C(max), but did not effect AUC. Further investigation of the incorporation of population pharmacokinetic approaches in food effect studies is warranted.
Shepard
Dale R
DR
University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USA.
Mani
Sridhar
S
Kastrissios
Helen
H
Learned-Coughlin
Susan
S
Smith
Deborah
D
Ertel
Phillip
P
Magnum
Steve
S
Janisch
Linda
L
Fleming
Gini F
GF
Schilsky
Richard L
RL
Ratain
Mark J
MJ
D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D042943:Dihydrouracil Dehydrogenase (NADP); D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics*; D018565:Food-Drug Interactions / Q000502:physiology*; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D011153:Population; D013810:Therapeutic Equivalency; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C073482:eniluracil; D014498:Uracil; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil