Close correlation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate, an intracellular active metabolite, to the therapeutic efficacy of N(4)-behenoyl-1-beta-D-arabinofuranosylcytosine therapy for acute myelogenous leukemia.
N(4)-Behenoyl-1-beta-D-arabinofuranosylcytosine (BHAC), a prodrug of 1-beta-D-arabinofuranosylcytosine, is used effectively for the treatment of leukemia in Japan. BHAC therapy may be more effective if it is delivered in conjunction with monitoring of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP), the intracellular active metabolite of ara-C derived from BHAC. However, previous monitoring methods for ara-CTP were insufficiently sensitive. Here, using our new sensitive method, we evaluated the ara-CTP pharmacokinetics in relation to the therapeutic response in 11 acute myelogenous leukemia patients who received a 2-h infusion of BHAC (70 mg / m(2)) in combination remission induction therapy. ara-CTP could be monitored at levels under 1 mM. BHAC maintained effective levels of plasma ara-C and intracellular ara-CTP for a longer time, even compared with historical values of high-dose ara-C. The area under the concentration-time curve of ara-CTP was significantly greater in the patients with complete remission than in the patients without response. This greater amount of ara-CTP was attributed to the higher ara-CTP concentrations achieved in the responding patients. There was no apparent difference of plasma ara-C pharmacokinetics between the two groups. Thus, for the first time, the ara-CTP pharmacokinetics was evaluated in relation to the therapeutic effect of BHAC, and the importance of ara-CTP was proven. Administration of optimal BHAC therapy may require monitoring of the ara-CTP pharmacokinetics in each individual patient.
Yamauchi
T
T
First Department of Internal Medicine, Fukui Medical University, 20 Shimoaizuki, Matsuoka, Fukui 910-1193, Japan. tyamauch@fmsrsa.fukui-med.ac.jp
Kawai
Y
Y
Goto
N
N
Kishi
S
S
Imamura
S
S
Yoshida
A
A
Urasaki
Y
Y
Fukushima
T
T
Iwasaki
H
H
Tsutani
H
H
Masada
M
M
Ueda
T
T
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001085:Arabinofuranosylcytosine Triphosphate / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D003561:Cytarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007424:Intracellular Fluid / Q000737:chemistry; D007951:Leukemia, Myeloid / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000737:chemistry*; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D012074:Remission Induction; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; C015019:enocitabine