1.Disposition of cisplatin derivatives -3H-cis-1,2-diaminocyclohexanedichloroplatinum (II) and 3H-cis-1,2-diaminocyclohexanemalonatoplatinum (II
Oswald CB1, Wyrick SD, Chaney SG, Shrewsbury RO, Hall IH. Res Commun Chem Pathol Pharmacol. 1989 Apr;64(1):41-58.
The disposition of 3H-cis-1,2-diaminocyclohexanedichloroplatinum (II) and 3H-cis-1,2-diaminocyclohexanemalonatoplatinum (II) was investigated in P388 tumor-bearing BDF1 mice. Fifteen minutes after IP administration of the drugs, the serum contained 12% of the 3H-chloride derivative and 20% of the malonate derivative. Both drugs distributed to all organs of the body but were not sequestered in any major internal organ. However, substantial amounts of the drugs were found in the carcass and skin. After 24 hr, approximately 43% of the radioactivity was excreted in the urine. Only 5 to 8% of the radioactivity was eliminated in the feces. The radioactivity half-life (t1/2 beta) for the 3H-chloride derivative was estimated from urinary excretion data to be 22.7 hr, and 30.0 hr for the 3H-malonate derivative.
2.Determination of platinum-containing drugs in human plasma by liquid chromatography with reductive electrochemical detection.
Parsons PJ, Morrison PF, LeRoy AF. J Chromatogr. 1987 Jan 9;385:323-35.
The platinum complex cis-diamminedichloroplatinum(II)(cisplatin or CDDP), which is used successfully to treat various kinds of tumour, can be determined in human plasma ultrafiltrate using liquid chromatography with reductive electrochemical detection (LC-ED). Polarographic analyses of other platinum-containing drugs have been carried out, and the results indicate that some of them might be good candidates for detection using the ED method. cis-Dichloro-trans-dihydroxo-cis-bis-(isopropylamine)platinum(IV) (CHIP or JM-9), diammine(1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA or JM-8), and tetrachloro(trans-1,2-diaminocyclohexane)platinum(IV) (TCDCP), which are under evaluation for antitumour properties, have been investigated by this method. The results suggest that LC-ED may be a suitable technique for the determination of CHIP and TCDCP. The separation of cationic hydrolysis products from the neutral parent complex (CDDP) was carried out on reversed-phase columns, modified with alkylsulphonic acid ion-pair reagents.
3.Synthesis and characterization of N-methyliminodiacetato trans-R,R-, trans-S,S-, and cis-1,2-diaminocyclohexane platinum (IV) complexes: crys
Xu Q1, Khokhar AR. J Inorg Biochem. 1992 Nov 15;48(3):217-26.
The compounds, chloro(trans-R,R-1,2-diaminocyclohexane) (N-methyliminodiacetato)platinum(IV) chloride, chloro(trans-S,S-1,2-diaminocyclohexane)(N-methyliminodiacetato) platinum(IV) chloride, and chloro(cis-1,2-diaminocyclohexane)(N-methyliminodiacetato)platinum (IV) chloride, were prepared and characterized by elemental analysis, IR, and 195Pt NMR. The crystal structure of one of these three compounds, chloro(trans-R,R-1,2-diaminocyclohexane) (N-methyliminodiacetato) platinum(IV) chloride, was determined by x-ray single crystal diffraction. This compound is particularly interesting because the 1,2-diaminocyclohexane (DACH) ring is in a twist-boat configuration rather than the chair configuration previously reported for other DACH platinum compounds. The crystal structure consists of two independent cations and anions, with all atoms between these two independent molecules (except those in the chiral DACH) related by a pseudo-inversion center.
4.Lipophilic cisplatin analogues entrapped in liposomes: role of intraliposomal drug activation in biological activity.
Perez-Soler R1, Khokhar AR. Cancer Res. 1992 Nov 15;52(22):6341-7.
cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (NDDP), a lipophilic cisplatin analogue containing two branched leaving groups of 10 carbon atoms, is undergoing clinical evaluation in a liposomal formulation. In previous studies, NDDP entrapped in multilamellar vesicles composed of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) at a 7:3 molar ratio was non-nephrotoxic in humans, not cross-resistant with cisplatin in different in vitro and in vivo systems, and more active than cisplatin against murine models of experimental liver metastases whereas free NDDP was devoid of in vivo antitumor activity at the optimal dose of L-NDDP and barely active at higher doses. To elucidate the mechanisms by which the liposomal carrier enhances the biological properties to this class of antitumor agents, we studied the effect of the liposome composition, size of the branched leaving groups of the platinum compound, and pH and composition of the aqueous phase on the entrapment efficiency, drug leakage, drug stability, and in vivo toxicity and antitumor activity of different liposomal formulations of these agents.