The plasma and cerebrospinal fluid (CSF) pharmacokinetics of arabinosyl-5-azacytidine (AAC) were studied in rhesus monkeys following a 15-min, 1-h, or 12-h i.v. infusion of 200 mg/kg. No clinically significant toxicity was observed with these schedules. The plasma elimination of AAC is rapid and characterized by a triphasic decay with t½α = 3.6–5.4 min, t½β = 18–24 min, and t½γ = 94–144 min for the above infusion schedules. The CSF penetration of AAC as measured by the CSF:plasma C96 ratio for the 12-h infusion was 0.15.

The stability of AAC in pooled plasma, phosphate buffered saline, and RPMI 1640 culture media at 37°C was compared with the terminal half-life of AAC observed in vivo. The shorter in vitro AAC half-life in plasma with or without tetrahydrouridine versus that in phosphate buffered saline suggests that the terminal half-life of AAC in vivo is most likely a result of enhanced nucleophilic attack and hydrolytic degradation of the unstable triazine ring in plasma.

A triexponential equation modeling the disappearance of AAC was constructed from the in vivo experimental data. Use of this equation in computer-aided simulations of current Phase I doses and schedules of AAC correctly predicts the human plasma concentrations which have been observed. The preclinical pharmacokinetic data provided here may be useful in helping to develop rational human studies with specific concentration × time goals.

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©1988 American Association for Cancer Research.
1988
American Association for Cancer Research, Inc.