Effect of tetrahydrouridine on the clinical pharmacology of 1-β-D-arabinofuranosylcytosine when both drugs are coinfused over three hours

When 1-beta-D-arabinofuranosylcytosine (ara-C), 25 mg/m2, is infused over 3 h together with tetrahydrouridine (THU) at 10 to 350 mg/m2 to heavily pretreated patients with solid tumors, Michaelis-Menten type kinetic values are observed with leveling off of delta area under the curve, delta ara-C leve...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1988-03, Vol.48 (5), p.1337-1342
Main Authors: KREIS, W, CHAN, K, ANDREEFF, M, VINCIGUERRA, V, BUDMAN, D. R, SCHULMAN, P, ALLEN, S, WEISELBERG, L, LICHTMAN, S, HENDERSON, V, FREEMAN, J, DEERE, M
Format: Article
Language:English
Subjects:
Adult
Aged
Antineoplastic agents
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Biological and medical sciences
Bone Marrow - drug effects
Chemotherapy
Cytarabine - administration & dosage
Cytarabine - adverse effects
Cytarabine - pharmacokinetics
Deamination
Female
Half-Life
Humans
Male
Medical sciences
Middle Aged
Pharmacology. Drug treatments
Tetrahydrouridine - administration & dosage
Tetrahydrouridine - pharmacology
Uridine - analogs & derivatives
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Summary:When 1-beta-D-arabinofuranosylcytosine (ara-C), 25 mg/m2, is infused over 3 h together with tetrahydrouridine (THU) at 10 to 350 mg/m2 to heavily pretreated patients with solid tumors, Michaelis-Menten type kinetic values are observed with leveling off of delta area under the curve, delta ara-C levels at 3 h, and delta total body clearance after 150 mg/m2 of THU. When the ara-C dose was increased to 50, 75, and 100 mg/m2 coinfusion of 250 or 350 mg/m2 of THU significantly increased plasma ara-C at peak and area under the curve. In contrast, total body clearance and volume of distribution decreased significantly. At 100 mg/m2 of ara-C coinfused with high doses of THU, i.e., at 350 mg/m2, the pharmacokinetics of plasma ara-C was changed from a biphasic decay of plasma ara-C at peaks (control) to a curve similar or identical to a monophasic curve, indicating that THU not only inhibits deamination but also changes the distribution of ara-C. This combination provides plasma ara-C levels (greater than or equal to 10 microM) comparable to high dose ara-C at 1 g/m2. Such plasma ara-C levels are considered to be sufficient for saturation of the kinases catalyzing the production of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate. This reduced ara-C dose necessary to achieve saturation of kinases also reduces plasma 1-beta-D-arabinofuranosyluracil levels substantially. Toxicity of this combination was predominantly confined to bone marrow and gastrointestinal toxicity.
ISSN:0008-5472
1538-7445