Clinical pharmacology of O2,2'‐cyclocytidine

Two metabolites of 2‐14C‐cyclocytidine (cyclo‐C) were found in the plasma and urine and a hydrolytic product, arabinosylcytosine (ara‐C), and its deaminated product, arabinosyluracil (ara‐U), were found in patients with cancer; 80% of the dose was found in urine in 24 hr, 70% as cyclo‐C and 10% as ara‐C and ara‐U. The plasma disappearance curve of ara‐C is curvilinear; the half‐life of ara‐C estimated from the terminal phase is 8 hr. By 6 hr, the ara‐C level is 0.35 µg/ml and falls exponentially to 0.06 µ/ml by 24 hr. Plasma concentration ratios of ara‐U to ara‐C are 0.1 to 0.3, 0.3 to 0.4, and 1.1 to 1.3 at 10 min, 1 hr, and 4 hr following intravenous injection of cyclo‐C at 200 mg/m2. Five min after an equal dose of ara‐C, this ratio is approximately 2, and by 4 hr, plasma ara‐C levels are immeasurable. After intramuscular and subcutaneous administration, cyclo‐C is rapidly absorbed. The plasma disappearance curves of the cyclo‐C hydrolytic product, ara‐C, are similar to those of the intravenous route. Intramuscularly, subcutaneously, and intravenously cyclo‐C should be equally effective. Intrathecal injections of cyclo‐C (50 mg/m2) result in an effective ara‐C level (0.1 µ/ml) in cerebrospinal fluid (CSF) at 24 hr. When cyclo‐C is given orally to fasting patients, less than 15% of the dose is excreted in urine in 24 hr and none can be detected in the plasma.

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