Effect of amsacrine on ara-CTP cellular pharmacology in human leukemia cells during high-dose cytarabine therapy.
The combination of high-dose cytarabine (ara-C) and amsacrine (m-AMSA) is effective treatment for relapsed adult acute leukemia. Studies were performed to determine if m-AMSA affected the pharmacokinetics of the active triphosphate ara-CTP in HL-60 and K562 cells in culture. No significant differences were observed in accumulation, rate of elimination, or total intracellular exposure to ara-CTP in cultures treated with 100 microM ara-C alone or in combination with 1 microM m-AMSA. In clinical investigations, the accumulation and retention of ara-CTP in circulating leukemic cells were studied in five patients after two serial doses of ara-C (3 g/m2 infused over 2 hours) and in six additional patients in whom the second dose of ara-C was accompanied by an infusion of m-AMSA (30 mg/m2 infused over 1 hour). While substantial differences were observed in the cellular pharmacokinetics of ara-CTP among patients, the rate of ara-CTP elimination and the total intracellular exposure to ara-CTP in individuals were remarkably similar after each ara-C infusion. Infusion of m-AMSA with the second dose of ara-C did not significantly affect the cellular pharmacokinetics of ara-CTP. These studies demonstrate the feasibility and utility of conducting investigations of the cellular pharmacology of drug-drug interactions in human leukemic cells during therapy.
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000677:Amsacrine / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism*; D001088:Arabinonucleotides / Q000378:metabolism*; D002478:Cells, Cultured; D003561:Cytarabine / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged
D001088:Arabinonucleotides; D000677:Amsacrine; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate