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Identification of cis-Dichloro-bis-isopropylamine platinum(II) as a Major Metabolite of iproplatin in Humans¹

Department of Clinical Pharmacology and Therapeutics [L. P., J. W. C. P. J. C.], Department of Experimental Therapeutics [J. W. C.], and Department of Biophysics Research [G. B. C., S. P. D.], Roswell Park Memorial Institute, Buffalo, New York 14263

Iproplatin is a quadrivalent second-generation platinum complex undergoing clinical evaluation. In plasma and urine of patients receiving this drug, iproplatin- and platinum-containing metabolites of iproplatin were separated by reverse-phase gradient high performance liquid chromatography. One of the metabolites was identified by cochromatography and electron impact mass spectrometry as cis-dichloro-bis-isopropylamineplatinum(II), a metabolite formed by reduction of iproplatin. Incubation of iproplatin with ascorbic acid and cysteine, in vitro, indicates that iproplatin can be easily reduced to cis-dichloro-bis-isopropylamineplatinum(II) by reducing agents. It is hypothesized that the reduction of the quadrivalent complex iproplatin to cis-dichloro-bis-isopropylamineplatinum(II) occurs intracellularly.

¹ This work was supported by grants from USPHS (CA-21071) and Bristol Myers Company.

² To whom requests for reprints should be addressed, at Department of Clinical Pharmacology and Therapeutics, Roswell Park Memorial Institute, 666 Elm Street, Buffalo, NY 14263.

Received 11/23/87. Revised 3/14/88. Accepted 3/18/88.