An animal model for the study of chronopharmacokinetics of drugs and application to methotrexate and vinorelbine.

Abstract:

:An animal model was designed to study the chronopharmacokinetics of intravenous drugs and applied to anticancer agents vinorelbine (VNB) and methotrexate (MTX). Each experiment was performed on four pigs housed in a standardized light-dark cycle (12:12). Four pigs received a 0.16-mg bolus of VNB, followed by a 60-h continuous infusion at 0.48 mg/h. After hydration and urine alkalinization, four other pigs received a 2 mg/kg bolus of MTX, followed by two concomitant 60-h continuous infusions, one with MTX (8 mg/kg/h) and the other for hydration and folinic acid rescue (1.5 mg/kg/24 h). Serum cortisol was determined in each blood sample collected in these pigs. Blood samples were collected each hour for 60 h. The infusion flow rates and drug solution concentrations were controlled throughout the experiments. Analysis of VNB serum concentrations did not show any circadian rhythm of VNB serum concentrations. One pig administered MTX exhibited severe toxicity. Interestingly, no circadian rhythm of serum cortisol concentration was observed in this pig, whereas the three others exhibited a statistically significant cortisol circadian rhythm with a peak secretion in the morning. Two of these three pigs showed a significant 24-h rhythm of MTX with acrophase occurring at approximately 1:00 PM in both. The maximal concentration was found at 12:00 AM in the third pig. After the data were pooled, a highly significant (P < 0.01) circadian rhythm in MTX serum concentrations (57%) was found, with acrophase at midday. The pig represents a useful model for the study of chronopharmacokinetics of drugs given intravenously in human. The MTX chronokinetic variation found herein may be of interest for the improvement of chemotherapy in cancer patients.

journal_name

Toxicol Appl Pharmacol

authors

Prémaud A,Rousseau A,Gicquel M,Ragot S,Manceau J,Laurentie M,Marquet P

doi

10.1006/taap.2002.9467

subject

Has Abstract

pub_date

2002-09-15 00:00:00

pages

189-97

issue

3

eissn

0041-008X

issn

1096-0333

pii

S0041008X02994676

journal_volume

183

pub_type

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