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Spontaneous or imposed circadian changes in plasma concentrations of 5‐fluorouracil coadministered with folinic acid and oxaliplatin: Relationship with mucosal toxicity in patients with cancer
Author(s) -
Metzger Gérard,
Massari Claire,
Etienne MarieChristine,
Comisso Martine,
Brienza Silvano,
Touitou Yvan,
Milano Gérard,
Bastian Gérard,
Misset Jean Louis,
Lévi Francis
Publication year - 1994
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1994.123
Subject(s) - folinic acid , oxaliplatin , fluorouracil , pharmacokinetics , pharmacology , circadian rhythm , chemistry , elimination rate constant , mucositis , bioavailability , toxicity , antimetabolite , propofol , medicine , chemotherapy , colorectal cancer , cancer , volume of distribution
Pharmacokinetics of total platinum, 5‐fluorouracil, l ‐folinic and d ‐folinic acid, and 5‐methyltetrahydrofolate were studied in plasma from nine patients with advanced colorectal cancer treated with oxaliplatin (20 mg/m 2 /day), 5‐fluorouracil (600 mg/m 2 /day), and folinic acid (300 mg/m 2 /day). Drugs were administered with a programmable‐in‐time pump by continuous infusion for 5 days. We compared two drug delivery schedules: constant rate versus chronomodulated rate with peak of oxaliplatin at 4 PM and peak of 5‐fluorouracil and folinic acid at 4 AM. In the chronomodulated schedule, plasma concentrations of the drugs paralleled the pump functioning: maximum platinum concentration near 4 PM, and maximum 5‐fluorouracil and folate concentrations near 4 AM. When drugs were administered at a constant rate, mean plasma concentration of 5‐fluorouracil varied in a circadian manner each treatment day, that is, a peak at 4 AM (≈800 ng/ml) and a trough at 1 PM (≈100 ng/ml). Mean plasma levels of total platinum and folate compounds increased over the first 24 hours. Total platinum mean level and that of the inactive‐folinic acid isomer reached a constant plasma concentration, whereas biologically active folates exhibited circadian variation in their plasma concentrations (peak around 7 AM, trough near 6 PM, and amplitude ≈ 10%). Severe mucositis was exhibited by all four patients on the flat schedule, but only by one on the chronomodulated schedule (p < 0.008). Individual pharmacokinetic and toxicity data showed that patients with circadian rhythms in 5‐fluorouracil concentrations were least sensitive to 5‐fluorouracil–related toxicity. Thus amplification or induction of such rhythm in 5‐fluorouracil exposure may permit dose escalation. Clinical Pharmacology and Therapeutics (1994) 56, 190–201; doi: 10.1038/clpt.1994.123