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Titolo:
REVERSIBLE AND IRREVERSIBLE INTERACTIONS OF A CISPLATIN ANALOG BEARING A 1,2-DIPHENYLETHYLENEDIAMINE LIGAND WITH PLASMA AND PLASMA-PROTEINSIN-VITRO
Autore:
BEDNARSKI PJ; KRATOCHWIL NA; OTTO AM;
Indirizzi:
UNIV REGENSBURG,FAK CHEM PHARM,INST PHARM,LEHRSTUHL PHARMAZEUT CHIM 2D-93040 REGENSBURG GERMANY
Titolo Testata:
Drug metabolism and disposition
fascicolo: 3, volume: 22, anno: 1994,
pagine: 419 - 427
SICI:
0090-9556(1994)22:3<419:RAIIOA>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
SERUM-ALBUMIN; METAL-COMPLEXES; CULTURE MEDIUM; PLATINUM; BINDING; PHARMACOKINETICS; TETRAPLATIN; GLUTATHIONE; ANTITUMOR; INVITRO;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
40
Recensione:
Indirizzi per estratti:
Citazione:
P.J. Bednarski et al., "REVERSIBLE AND IRREVERSIBLE INTERACTIONS OF A CISPLATIN ANALOG BEARING A 1,2-DIPHENYLETHYLENEDIAMINE LIGAND WITH PLASMA AND PLASMA-PROTEINSIN-VITRO", Drug metabolism and disposition, 22(3), 1994, pp. 419-427

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 acytotoxic 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 atspecific 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 18/09/20 alle ore 16:44:29