title: Lack of effect of interferon alpha 2a upon fluorouracil pharmacokinetics.
abstract: The disposition of 5-fluorouracil (FUra) was studied in 19 colorectal cancer patients during treatment with FUra and high-dose leucovorin (LV) with or without interferon alpha 2a (IFN-alpha). All received LV 200 mg m-2 over 2 h, then FUra 400 mg m-2 over 5 min then FUra 400 mg m-2 over 22 h, repeated on day 2, on a 14 day cycle. Nine patients also received IFN-alpha 6 MU every 48 h, starting at least 2 weeks before the study. Series of 14 blood samples were assayed for FUra by reversed-phase high-performance liquid chromatography (HPLC). Minimum Akaike information criterion estimation was used to determine the simplest effective pharmacokinetic model. This consisted of a single compartment with first-order (linear) and Michaelis-Menten (non-linear) components to drug elimination. This model gave r2 > 0.98 in 19/20 data sets. With the Michaelis constant (KM) set at 15 microM, values were derived for the volume of distribution (Vd), the maximum rate of non-linear elimination (Vmax) and the first-order elimination rate constant (K1.e). Mean (+/- s.d.) values in control (no IFN-alpha) patients were: Vd 10.4 (+/- 1.9) l m-2, Vmax 182 (+/- 59) mumol l-1 h-1 and k1.e 4.35 (+/- 0.58) h-1. No significant differences were detected in patients receiving IFN-alpha, in whom the equivalent mean values were Vd 10.0 (+/- 0.9) l m-2, Vmax 141 (+/- 27) mumol l-1 h-1 and k1.e 3.96 (+/- 0.5) h-1. Mean trapezoidal AUC0-22 h was similar in the two groups (control patients 116 microM h, IFN-alpha patients 125 microM h). No significant correlations with renal or hepatic function were detected. These results, while not inconsistent with previous reports of a reduced rate of FUra elimination at higher IFN-alpha doses, suggest that any clinical effect of this moderate dose of IFN-alpha on FUra toxicity or activity is due to modulation at target cells, not to pharmacokinetic interaction.
authors.affiliation: Department of Medical Oncology, St Bartholomew's Hospital, London, UK.
authors.forename: M T
authors.initials: MT
authors.lastname: Seymour
authors.forename: N
authors.initials: N
authors.lastname: Patel
authors.forename: A
authors.initials: A
authors.lastname: Johnston
authors.forename: S P
authors.initials: SP
authors.lastname: Joel
authors.forename: M L
authors.initials: ML
authors.lastname: Slevin
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001825:Body Fluid Compartments; D015179:Colorectal Neoplasms / Q000097:blood / Q000378:metabolism* / Q000628:therapy; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005069:Evaluation Studies as Topic; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D007700:Kinetics; D002955:Leucovorin / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011994:Recombinant Proteins
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D002955:Leucovorin; D005472:Fluorouracil