PLASMA AND LEUKEMIC-CELL PHARMACOKINETICS OF HIGH-DOSE N-4-BEHENOYL-1-BETA-D-ARABINOFURANOSYLCYTOSINE IN ACUTE-LEUKEMIA PATIENTS

The pharmacokinetics of N-4-behenoyl-1-beta-D-arabinofuranosylcytosine (BHAC), a lipophilic antitumor analog of 1-beta-D-arabinofuranosylcyt osine (ara-C), was investigated, by assay of plasma and leukemic cells of ten acute leukemic patients receiving 60-minute in tra venous (IV) infusion of 700 mg/m(2) BHAC, for BHAC and 1-beta-D-arabinofuranosylc ytosine S-triphosphate (ara-CTP) by high-performance liquid chromatogr aphy, ara-C by radioimmunoassay, and 1-beta-D-arabinofuranosyluracil ( ara-U) by gas chromatography-mass fragmentography. The plasma concentr ation of BHAC reached a maximum (173.4 +/- 75.3 mu g/mL) at the end of the infusion and then declined in a biphasic pattern with an initial- phase half-life (t1/2 alpha) of 1.00 +/- .36 hours and a second-phase half-life (t1/2 beta) of 4.28 +/- 2.35 hours. That of ara-C similarly reached a maximum (102.2 +/- 39.9 mg/mL) at the end of the infusion an d then declined with t1/2 alpha of 1.37 +/- 1.11 hours and t1/2 beta o f 11.2 +/- 4.31 hours. Intracellular ara-CTP concentration increased i n a linear-accumulation manner for the first 4 hours after the infusio n, reached a maximum of .081 +/- 1.12 mu g/10(7) cells at approximatel y 7 hours, and then declined very slowly in accordance with a one-comp ortment model with t1/2 of 13.56 +/- 9.62 hours.