Clinical pharmacology of 1-beta-d-arabinofuranosyl cytosine.

Abstract

Pharmacologic studies were performed in man with tritiated 1‐β‐D‐arabinofuranosyl cytosine (ara‐C). Most of the plasma and urine radioactivity was in 1‐f3‐D‐arabinofuranosyl uracil (ara‐U), and all of the radioactivity could be accounted for as ara‐C and ara‐U. The plasma disapperance curve of ara‐C when plotted on a semilog scale was biphasic with an initial fast phase (mean half‐time 12 minutes) and a slower second phase (mean half‐time 111 minutes). There was a linear correlation between the dose and plasma concentration of ara‐C. The initial plasma ara‐U to ara‐C ratio was lower at the high doses, suggesting saturation of ara‐C deaminase activity. Eighty per cent of the radioactivity was recovered in the urine by 24 hours, 8 per cent as ara‐C, and 72 per cent as ara‐U. Prior treatment with ara‐C had no effect on the pharmacology of ara‐C. The plasma ara‐C deaminase activity was very low. The total amount in plasma was less than one per cent of that present in the liver. The ara‐C deaminase activity of red blood cells (RBC) of normal subjects was 7 per cent that of the liver, and the RBC of solid tumor patients contained significantly higher enzyme activity. Following a loading dose, ara‐C was given by constant intravenous infUSion. This resulted in constant plasma ara‐C levels which were dose related. At steady state the cerebrospinal fluid (CSF) to plasma ratio of ara‐C was 0.4. Intrathecal injection of ara‐C resulted in high initial CSF levels and an exponential decrease with a half‐time of 2 hours. This very long half‐time as compared to the plasma is a function of the very low ara‐C deaminase activity in CSF and brain.