Oral antitumour activity in murine L1210 leukaemia and pharmacological properties of liposome formulations ofN 4-alkyl derivatives of 1-β-d-arabinofuranosylcytosine
Cyclocytidine (cyclo-C) and arabinosylcytosine (ara-C) were compared as to distribution and metabolism in dogs after administration by the intravenous, subcutaneous, intramuscular, and oral routes. After cyclo-C, two metabolites were found in the plasma and urine--a hydrolytic product, ara-C, and its deaminated product, arabinosyluracil (ara-U). The urinary excretion of cyclo-C is rapid; Five hours after parenteral administration, 60% of the given drug is excreted; 45% as cyclo-C, 10% as ara-C, and about 5% as ara-U. In contrast, after similar injections of ara-C, 45% of the drug is excreted; 33% as ara-C and 12% as ara-U. When compared with those in human and mouse tissues, the deoxycytidine deaminase levels in dog tissues are extremely low. This agrees with the finding of low ara-U levels in dog plasma and urine after administering cyclo-C or ara-C. Regardless whether cyclo-C or ara-C is injected, the plasma decay curve of the resultant ara-C is biphasic, with calculated half-lives of 40 min and 2-2.5 hr. However, if ara-C is given, the plasma ara-C peak level is higher. Higher ara-C levels are also maintained throughout the measured 5 hr. There are no differences in pharmacologic disposition after iv, sc, or im administration of ara-C. This is also true for cyclo-C. These findings suggest that for both drugs, the above routes of administration may be equally effective. Neither cyclo-C nor ara-C is well absorbed after oral administration, and the drug concentration in the plasma is too low to be measurable. Whether the dog is fasted overnight or fed, the drug is excreted slowly. In 5 hr. no more than 3% is excreted, and by 12 hr. only 10% is excreted.