title: In vivo accumulation of etoposide in peripheral leukemic cells in patients treated for acute myeloblastic leukemia; relation to plasma concentrations and protein binding.
abstract: Since etoposide interacts with the nuclear enzyme topoisomerase II, the drug concentrations in the malignant cells during chemotherapy may have clinical correlates. Plasma protein binding of etoposide is extensive (94%) and alterations of the non-proteinbound fraction affect pharmacokinetic behavior of the drug. The pharmacokinetics of etoposide was therefore studied in plasma, total and non-proteinbound concentrations, and in leukemic cells isolated from peripheral blood samples from 22 patients after the first dose of the induction treatment for acute myelocytic leukemia. Fourteen patients received 100 mg/m2 and eight patients 200 mg/m2 as a 1 h infusion. The mean area under the concentration versus time curve AUC(0-infinity) in plasma was at the lower dose level 78.4 +/- 29.1 (mean +/- S.D.) micrograms/ml x h and 201.0 +/- 56.5 micrograms/ml x h at the higher dose level. The fraction of non-proteinbound etoposide in plasma was 5.2 +/- 3.4 and 5.4 +/- 2.1% in the two treatment groups. AUC(0-16h) in leukemic cells was 8.4 +/- 8.7 and 22.4 +/- 12.1 micrograms/ml x h at the two dose levels, respectively. The cellular etoposide concentration was 12.1 +/- 7.9 and 14.7 +/- 5.1% of the plasma concentration at the end of the infusion. The interpatient variability in cellular drug levels was considerable and exceeded the variability in plasma concentrations. Cellular accumulation of etoposide could be important for treatment outcome.
authors.affiliation: Department of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden.
authors.forename: E K
authors.initials: EK
authors.lastname: Liliemark
authors.forename: J
authors.initials: J
authors.lastname: Liliemark
authors.forename: B
authors.initials: B
authors.lastname: Pettersson
authors.forename: A
authors.initials: A
authors.lastname: Gruber
authors.forename: M
authors.initials: M
authors.lastname: Björkholm
authors.forename: C
authors.initials: C
authors.lastname: Peterson
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001752:Blast Crisis / Q000097:blood / Q000188:drug therapy; D001798:Blood Proteins / Q000378:metabolism*; D003561:Cytarabine / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism; D059005:Topoisomerase II Inhibitors
chemical_list: D001798:Blood Proteins; D012709:Serum Albumin; D059005:Topoisomerase II Inhibitors; D003561:Cytarabine; D005047:Etoposide; D008942:Mitoxantrone