Clinical pharmacology of 0²,2′-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 inpatients 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 μ/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, I 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.