Pharmacokinetic studies during phase I trials of high-dose thymidine infusions

Thymidine infusions (75 g/sq m/24 hr) were administered to 12 cancer patients as part of a Phase I study. Thymidine and thymine measurements, by high-pressure liquid chromatography, were made on plasma and urine from eight of these patients. Only the pharmacokinetic aspects of these studies are repo...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1979-12, Vol.39 (12), p.4777-4781
Main Authors: Zaharko, D S, Bolten, B J, Chiuten, D, Wiernik, P H
Format: Article
Language:English
Subjects:
Drug Evaluation
Female
Humans
Infusions, Parenteral
Kidney - metabolism
Male
Metabolic Clearance Rate
Neoplasms - drug therapy
Neoplasms - metabolism
Thymidine - administration & dosage
Thymidine - metabolism
Thymine - metabolism
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Summary:Thymidine infusions (75 g/sq m/24 hr) were administered to 12 cancer patients as part of a Phase I study. Thymidine and thymine measurements, by high-pressure liquid chromatography, were made on plasma and urine from eight of these patients. Only the pharmacokinetic aspects of these studies are reported in this paper. Millimolar thymidine and thymine concentrations were achieved in all patients and maintained for 120 hr during each of three courses of infusion. The half-life of thymidine was approximately 100 min following cessation of infusion. The half-life of thymine was much longer but could not be accurately determined because it did not decline as a first-order rate function. The cerebrospinal fluid:plasma ratios at steady state for thymidine and thymine were 0.29 and 1.03, respectively. Total body clearance of thymidine ranged from 95 to 266 ml/min/sq m, and 41 to 67% was by kidney clearance of intact thymidine. Calculations and comparison to other studies at lower infusion rates (micromolar plasma thymidine) indicate that thymidine is metabolized significantly by organs in addition to the liver and that, at millimolar plasma thymidine, total body metabolic processes of thymidine are saturated as is the secretory portion of kidney clearance.
ISSN:0008-5472