BEDNARSKI, PJ and KRATOCHWIL, NA and OTTO, AM (1994) REVERSIBLE AND IRREVERSIBLE INTERACTIONS OF A CISPLATIN ANALOG BEARING A 1,2-DIPHENYLETHYLENEDIAMINE LIGAND WITH PLASMA AND PLASMA-PROTEINS IN-VITRO. DRUG METABOLISM AND DISPOSITION, 22 (3). pp. 419-427. ISSN 0090-9556,
Full text not available from this repository.Abstract
The cisplatin analog [meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl) ethylenediamine]dichloroplatinum(II) [PtCl2(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 degrees C [PtCl2(1)] is >99% reversibly bound to proteins in plasma. At 0 degrees C [PtCl2(1)] reversibly binds to albumin at specific binding sites not shared by 1. By use of HPLC the in vitro half-life of total [PtCl2(1)] in plasma was found to be 35 min at 37 degrees C, which is similar to 1/3 the half-life reported for cisplatin under similar conditions. To understand this decreased stability, irreversible reactions of [PtCl2(1)] with albumin and plasma globulins were investigated. The reaction rate of [PtCl2(1)] with albumin is independent of the protein concentration and is comparable to the rate of the first Pt-Cl hydrolysis reaction. Thus, [PtCl2(1)], like cisplatin, reacts irreversibly with albumin through a solvent-assisted S(N)2 substitution pathway. Because the hydrolysis rate for [PtCl2(1)] is 40% slower than for cisplatin, irreversible reactions of [PtCl2(1)] with albumin cannot account for the decreased stability of the compound in plasma. alpha-Globulins undergo substitution reactions with [PtCl2(1)] by both solvent-assisted and direct S(N)2 pathways. The half-life of [PtCl2(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 [PtCl2(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. [PtCl2(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 [PtCl2(1)] is efficiently metabolized to 1 in plasma (t(1/2) = 70 min) indicates that 1 will also be a metabolite in vivo.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SERUM-ALBUMIN; METAL-COMPLEXES; CULTURE MEDIUM; PLATINUM; BINDING; PHARMACOKINETICS; TETRAPLATIN; GLUTATHIONE; ANTITUMOR; INVITRO; |
| Depositing User: | Dr. Gernot Deinzer |
| Last Modified: | 19 Oct 2022 08:40 |
| URI: | https://pred.uni-regensburg.de/id/eprint/53293 |
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