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Plasma and cellular pharmacokinetics of m‐AMSA related to in vitro toxicity towards normal and leukemic clonogenic bone marrow cells (CFU‐GM, CFU‐L)
Author(s) -
Linssen P.,
Brons P.,
Knops G.,
Wessels H.,
Witte T.
Publication year - 1993
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/j.1600-0609.1993.tb00083.x
Subject(s) - clonogenic assay , pharmacokinetics , bone marrow , toxicity , in vitro , chemistry , ic50 , pharmacology , incubation , andrology , medicine , biochemistry
Plasma and cellular pharmacokinetics of m‐AMSA were investigated in 5 patients with acute leukemia, using HPLC. The pharmacokinetic data served as a guideline for in vitro toxicity tests on clonogenic bone marrow cells. m‐AMSA was administered as a 3‐hour intravenous infusion of 100 mg/m 2 . Median plasma and nucleated blood cell peak concentrations were 1.25 and 6.36 μg/ml followed by biphasic elimination with a median T1/2αα of 1.6 h and 0.3 h and a median T1/2β of 5.0 h and 5.0 h respectively. Median plasma and cellular area under the curve (AUC) for a 24‐h period amounted 6.2 μug·h/ml and 49.8 μg·h/ml respectively. In vitro cellular uptake was maximal at least within 30 minutes. No differential toxicity for CFU‐GM and CFU‐L was observed in relation to exposure time. Median IC 50 for CFU‐GM and CFU‐L was 2.2, 1.8 and 1.6 μg/ml after incubation periods of resp. 0.08, 4 and 24 h. The corresponding m‐AMSA concentration × time products to achieve 50% inhibition (IAUC 50 ) were 0.18, 7.2 and 38.4 μg·h/ml, respectively. 48‐h prestimulation of the clonogenic bone marrow cells with Human Placenta Conditioned Medium increased sensitivity (median 1.7 ×) after 4 h incubation with mAMSA. Short exposure provides maximal, concentration‐related, cellular uptake, resulting in effective inhibition of growth of clonogenic bone marrow cells.