Intracellular metabolites of cisplatin in the rat kidney.
The appearance of low-molecular-weight metabolites of cisplatin in the cytosol of cells from the cortex and outer medulla of the rat kidney has been examined using HPLC up to 24 h following cisplatin administration. Comparison was made between these metabolites and those present in plasma, urine and liver. The effect of sodium chloride (NaCl) pretreatment, which is known to reduce cisplatin-induced nephrotoxicity, on these metabolites was also investigated. Platinum levels in the kidney cortex and medulla and the cytosol reached maximal levels within 1 h of i.p. injection of 5 mg/kg cisplatin. At least six platinum species, including cisplatin, were present 1 h post-dosing, with the principal species being the parent drug; all of these species were either neutral or negatively charged. Although the concentration of most of the platinum species fell with time, that of one species eluting before cisplatin rose, and by 24 h it was the major metabolite. Cisplatin and two other major cytosolic platinum species were also present in urine and plasma, both of which also contained a number of charged species that were absent from the cytosol. The liver cytosol contained at least five metabolites 1 h post-dosing, but, in contrast to the kidney cytosol at the same time, the predominant species was that eluting before cisplatin and not cisplatin itself. One of the metabolites in the cytosol and urine had the same retention time as an adduct of cisplatin with glutathione and with cysteine. Urinary samples also contained a metabolite coeluting with aquated cisplatin. Pretreatment of animals with NaCl significantly reduced the platinum concentration in the kidney, with a corresponding decrease in the cytosolic metabolites; this may have contributed significantly to the reduction in cisplatin-induced nephrotoxicity after NaCl pretreatment. NaCl also significantly reduced a possible aquated species present in the urine, which may also have contributed to the reduction in nephrotoxicity. The data suggest that cisplatin itself may be the nephrotoxic species, since it is the intracellular platinum compound present in highest concentration during the early critical period after its administration.
Mistry
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Department of Biology and Biochemistry, Brunel University, Uxbridge, Middlesex, UK.
Lee
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McBrien
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D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000008:administration & dosage / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism*; D007668:Kidney / Q000166:cytology / Q000378:metabolism*; D007672:Kidney Cortex / Q000378:metabolism; D007679:Kidney Medulla / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D008970:Molecular Weight; D010984:Platinum / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D051381:Rats; D011919:Rats, Inbred Strains; D012965:Sodium Chloride / Q000494:pharmacology; D014018:Tissue Distribution
D012965:Sodium Chloride; D010984:Platinum; D002945:Cisplatin