In vivo and in vitro pharmacokinetic differences between four structurally closely related anthracyclines in hematopoietic cell subtypes in humans.
Minor differences in chemical structure of adriamycin (ADM), 4'-epiadriamycin (E-ADM), daunomycin (DNM), and 4-demethoxydaunomycin (D-DNM) lead to large differences between cellular and plasma pharmacokinetic parameters in vivo, as well as in cellular drug handling. Anthracyclines accumulated in cells to several hundred-fold the plasma concentration. Half-lives, as well as the ratio of parent drug/metabolite, differed markedly. The slopes of the in vivo cellular concentration-time curves after the end of the bolus injection resembled the efflux curves observed after a 5-min exposure in vitro. In vivo, the area under the cellular concentration-time curve (AUCc) for equimolar dosages was largest for ADM and smallest for D-DNM. In vitro however, cellular drug levels and AUCc were highest for D-DNM, followed by DNM, E-ADM, and ADM. Final cellular drug concentrations were 300-2500 times the medium concentration, with clearly higher values observed after the 360-min exposure. Minor structural differences were related to considerable variations in cellular drug handling, with different patterns in vivo and in vitro. These studies point to difficulties occurring in the in vitro experimental studies of in vivo pharmacokinetic properties of anthracyclines and stress the need for direct determination of target cell drug concentrations in vivo, in the search for the understanding of cell drug handling-related mechanisms of action of the anthracyclines.
Speth
P A
PA
Department of Medical Oncology, St. Radboud University Hospital, Nijmegen, The Netherlands.
Linssen
P C
PC
Termond
E F
EF
Boezeman
J B
JB
Wessels
H M
HM
Haanen
C
C
D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D001854:Bone Marrow Cells; D002851:Chromatography, High Pressure Liquid; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000145:classification / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure
D000903:Antibiotics, Antineoplastic