title: Clinical pharmacology of 1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate, an orally administered long-acting derivative of low-dose 1-beta-D-arabinofuranosylcytosine.
abstract: 1-beta-D-Arabinofuranosylcytosine-5'-stearylphosphate (cytarabine ocfosfate, stearyl-ara-CMP) is a newly synthesized 5'-alkylphosphate derivative of 1-beta-D-arabinofuranosylcytosine (ara-C), which is lipophilic, resistant to inactivation by deamination, and orally active. Pharmacology of this drug was studied in patients with hematological malignancies. The concentrations of stearyl-ara-CMP, ara-C (its active metabolite), and 1-beta-D-arabinofuranosyluracil (ara-U, its inactive metabolite) were determined by radioimmunoassay. When six patients received a single p.o. dose of the drug (500 mg/m2), stearyl-ara-CMP, ara-C, and ara-U could be detected in the plasma for at least 72 h afterwards. The plasma disappearance curve of stearyl-ara-CMP corresponded to a one-compartment open model with first-order absorption kinetics. The peak plasma level (Cmax) was 322 +/- 218 nM, and the predicted time to reach Cmax (Tmax) was 6.5 +/- 4.5 h, while the elimination half-life (t1/2) was very long (32.0 +/- 8.4 h). The plasma ara-C level increased slowly to a Cmax of 26.3 +/- 12.7 nM (Tmax, 13.3 +/- 4.7 h) after stearyl-ara-CMP administration. This level was quite low compared with that achieved by low-dose s.c. ara-C therapy, but ara-C persisted longer in the plasma in the former case, and the area under the curve was similar for both regimens. For ara-U, the Cmax, Tmax, and t1/2 were 483 +/- 315 nM, 23.6 +/- 4.0 h, and 19.6 +/- 5.3 h, respectively. No stearyl-ara-CMP was detected in the urine, and only 8.0% of the administered dose was excreted as ara-C and ara-U within 72 h. The stearyl-ara-CMP concentration in the cerebrospinal fluid was below the limit of detection in three patients without meningeal involvement at 6 h. During clinical use of stearyl-ara-CMP, macrocytic anemia was observed, and some patients also developed megaloblastic change of their erythroblasts, suggesting a mild and persistent cytostatic effect. In conclusion, p.o. therapy with stearyl-ara-CMP achieved prolonged maintenance of the plasma drug level. Thus, the drug released a very low dose of ara-C over a long period in plasma and tissues and had a prolonged mild antineoplastic effect in patients with hematological malignancies.
authors.affiliation: First Department of Medicine, Fukui Medical School, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ueda
authors.forename: K
authors.initials: K
authors.lastname: Kamiya
authors.forename: Y
authors.initials: Y
authors.lastname: Urasaki
authors.forename: S
authors.initials: S
authors.lastname: Wataya
authors.forename: Y
authors.initials: Y
authors.lastname: Kawai
authors.forename: H
authors.initials: H
authors.lastname: Tsutani
authors.forename: M
authors.initials: M
authors.lastname: Sugiyama
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000754:Anemia, Refractory, with Excess of Blasts / Q000188:drug therapy* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001088:Arabinonucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D003568:Cytidine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011087:Polycythemia Vera / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001088:Arabinonucleotides; C061162:1-arabinofuranosylcytosine-5'-stearylphosphate; D003568:Cytidine Monophosphate