Decomposition kinetics of cisplatin in human biological fluids.
Cisplatin is metabolized to high- and low-molecular mass complexes by exchanging of one or both chloride ligands with nucleophilic species. The decomposition of cisplatin and the formation of its metabolites in human biological fluids was investigated in-vitro. In nucleophile-free medium, cisplatin was decomposed by a reversible chloride ligand exchange reaction, which was dependent upon both chloride ion concentration and medium pH. The effect of pH was observed in the second-order rate constant for cisplatin re-formation, which was far smaller in neutral and alkaline media than in acidic media. In the medium containing nucleophilic species (glutathione, human albumin and globulin), cisplatin was irreversibly decomposed according to apparent first-order kinetics. The linear relationship between apparent decomposition rate constant and concentration of nucleophilic species suggested that nucleophilic species in biological fluids might react with cisplatin directly. Both high- and low-molecular mass metabolites were formed in human plasma and ascites; however, only a low-molecular mass metabolite was produced in urine. The faster decomposition of cisplatin and the greater ratio of fixed and mobile metabolites formed in plasma were mainly attributed to higher albumin concentration in plasma than in ascites and urine. The in-vitro decomposition of unchanged cisplatin and formation of high- and low-molecular mass metabolites in human biological fluids were simultaneously evaluated according to the kinetic model which combined both pathways via hydrolysis and by the direct reaction process with nucleophilic species.
Department of Biopharmaceutics, Meiji College of Pharmacy, Tokyo, Japan.
N
N
Nagai
R
R
Okuda
M
M
Kinoshita
H
H
Ogata
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D001711:Biotransformation; D002021:Buffers; D002712:Chlorides / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000737:chemistry* / Q000493:pharmacokinetics; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007700:Kinetics; D008954:Models, Biological; D010984:Platinum / Q000737:chemistry; D013054:Spectrophotometry, Atomic; D013696:Temperature
D000970:Antineoplastic Agents; D002021:Buffers; D002712:Chlorides; D010984:Platinum; D005978:Glutathione; D002945:Cisplatin