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Clinical Pharmacology of 1-β-D-Arabinofuranosylcytosine-5'-stearylphosphate, an Orally Administered Long-Acting Derivative of Low-Dose 1-β-D-Arabinofuranosylcytosine¹

First Department of Medicine, Fukui Medical School, Matsuoka, Fukui 910-11 [T. U., K. K., Y U., S. W., Y. K., H. T., T. N.], and Pharmacy Department, Osaka Red Cross Hospital, Tennohji, Osaka 543 [M. S.], Japan

² To whom requests for reprints should be addressed.

1-β-D-Arabinofuranosylcytosine-5'-stearylphosphate (cytarabine ocfosfate, stearyl-ara-CMP) is a newly synthesized 5-alky!phosphate derivative of 1-β-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-β-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 (C_max) was 322 ± 218 nM, and the predicted time to reach C_max (T_max) was 6.5 ± 4.5 h, while the elimination half-life (t) was very long (32.0 ± 8.4 h). The plasma ara-C level increased slowly to a C_max of 26.3 ± 12.7 nM (T_max, 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 C_max, T_max, and t 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 stearylara-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.

¹ Supported in part by a Grant-in-Aid from the Ministry of Health and Welfare, Japan.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 12/17/92. Accepted 11/ 1/93.

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