title: Effect of tetrahydrouridine on the clinical pharmacology of 1-beta-D-arabinofuranosylcytosine when both drugs are coinfused over three hours.
abstract: 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.
authors.affiliation: Department of Medicine, North Shore University Hospital, Cornell University Medical College, Manhasset, New York.
authors.forename: W
authors.initials: W
authors.lastname: Kreis
authors.forename: K
authors.initials: K
authors.lastname: Chan
authors.forename: D R
authors.initials: DR
authors.lastname: Budman
authors.forename: P
authors.initials: P
authors.lastname: Schulman
authors.forename: S
authors.initials: S
authors.lastname: Allen
authors.forename: L
authors.initials: L
authors.lastname: Weiselberg
authors.forename: S
authors.initials: S
authors.lastname: Lichtman
authors.forename: V
authors.initials: V
authors.lastname: Henderson
authors.forename: J
authors.initials: J
authors.lastname: Freeman
authors.forename: M
authors.initials: M
authors.lastname: Deere
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D003641:Deamination; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D013767:Tetrahydrouridine / Q000008:administration & dosage / Q000494:pharmacology*; D014529:Uridine / Q000031:analogs & derivatives*
chemical_list: D003561:Cytarabine; D013767:Tetrahydrouridine; D014529:Uridine