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 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.