Reversible and irreversible interactions of a cisplatin analog bearing a 1,2-diphenylethylenediamine ligand with plasma and plasma proteins in vitro
Bednarski, P.J.; Kratochwil, N.A.; Otto, A.M.
Drug Metabolism and Disposition the Biological Fate of Chemicals 22(3): 419-427
1994
ISSN/ISBN: 0090-9556 PMID: 7520852 Document Number: 434246
The cisplatin analog (meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl) ethylenediamine)dichloroplatinum(II) (PtCl-2(1)), by virtue of its estrogenic 1,2-diphenylethylenediamine ligand 1, was intended to function as a cytotoxic estrogen. This article reports on the reversible and irreversible interactions of this compound with plasma and plasma proteins in vitro. At 37 degree C (PtCl-2(1)) is gt 99% reversibly bound to proteins in plasma. At 0 degree C (PtCl-2(1)) reversibly binds to albumin at specific binding sites not shared by 1. By use of HPLC the in vitro half-life of total (PtCl-2(1)) in plasma was found to be 35 min at 37 degree C, which is apprx 1/3 the half-life reported for cisplatin under similar conditions. To understand this decreased stability, irreversible reactions of (PtCl-2(1)) with albumin and plasma globulins were investigated. The reaction rate of (PtCl-2(1)) with albumin is independent of the protein concentration and is comparable to the rate of the first Pt-Cl hydrolysis reaction. Thus, (PtCl-2(1)), like cisplatin, reacts irreversibly with albumin through a solvent-assisted S-N2 substitution pathway. Because the hydrolysis rate for (PtCl-2(1)) is 40% slower than for cisplatin, irreversible reactions of (PtCl-2(1)) with albumin cannot account for the decreased stability of the compound in plasma. alpha-Globulins undergo substitution reactions with (PtCl-2(1)) by both solvent-assisted and direct S-N2 pathways. The half-life of (PtCl-2(1)) in the presence of alpha-globulins at concentrations normally present in plasma (6-16 g/liter) is from 41 to 22 min. Thus, the reaction rate of (PtCl-2(1)) with alpha-globulins is great enough to explain why the compound is less stable in plasma than would be anticipated from its hydrolysis rate. (PtCl-2(1)) is efficiently metabolized to 1 in plasma, with a maximum conversion of ca. 40% being achieved by 4 hr. alpha-Globulins (maximum 16%) are the most, whereas albumin (maximum 6%) is the least effective protein at causing the conversion to 1. That (PtCl-2(1)) is efficiently metabolized to 1 in plasma (t-1/2 = 70 min) indicates that 1 will also be a metabolite in vivo.