Clinical pharmacology of N4-palmitoyl-1-beta-D-arabinofuranosylcytosine in patients with hematologic malignancies.
The pharmacokinetics of oral N4-palmitoyl-1-beta-D-arabinofuranosylcytosine (PLAC), a lipophilic and deaminase-resistant derivative of 1-beta-D-arabinofuranosylcytosine (ara-C), were determined in patients with hematologic malignancies. The concentration of ara-C and 1-beta-D-arabinofuranosyluracil (ara-U), metabolites of PLAC, were measured by radioimmunoassay and gas chromatography-mass spectrometry-mass fragmentography, respectively. The concentration of PLAC was determined by measuring ara-C, which was derived from PLAC by hydrolyzation. In six patients given an oral bolus of PLAC (300 mg/m2), the plasma-disappearance curve of PLAC corresponded to a one-compartment open model, including first-order absorption. The peak plasma level was 22.9 +/- 6.4 ng/ml, and the predicted time to reach the peak level was 2.5 +/- 1.0 h. The elimination half-life was 3.8 +/- 2.7 h. The plasma ara-C level increased slowly to 6.9 ng/ml during the 1st 2-3 h after administration and remained over 1.0 ng/ml for 12 h. Plasma ara-U was detectable for at least 24 h, with a peak concentration of 376 ng/ml at 6 h. Urinary PLAC excretion was below the limit of detection (5 ng/ml) in all cases. Prolonged urinary ara-C and ara-U excretion was detected, but the total recovery rate was low (6.7% in 24 h) and varied between patients. In spite of the lipophilic nature of the drug, the PLAC concentration in the cerebrospinal fluid, measured at 3 or 6 h, was below the limit of detection in all four patients with no meningeal involvement. This study showed low but persistent levels of PLAC in plasma and tissues, with a continuous release of small amounts of ara-C, which demonstrated antitumor activity in patients with hematologic malignancies.
Ueda
T
T
First Department of Medicine, Fukui Medical School, Japan.
Nakamura
T
T
Kagawa
D
D
Uchida
M
M
Domae
N
N
Sugiyama
M
M
Ueda
Y
Y
Sasada
M
M
Uchino
H
H
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001086:Arabinofuranosyluracil / Q000378:metabolism; D003561:Cytarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D006402:Hematologic Diseases / Q000188:drug therapy*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D011087:Polycythemia Vera / Q000188:drug therapy
D000970:Antineoplastic Agents; D003561:Cytarabine; D001086:Arabinofuranosyluracil; C047643:N(4)-palmitoyl cytarabine