Lack of nephrotoxicity of oral ammine/amine platinum (IV) dicarboxylate complexes in rodents.
The comparative nephrotoxicity of i.v. cisplatin, i.v. carboplatin and six p.o. ammine/amine Pt(IV) dicarboxylates was studied in rodents following single MTD treatments. In mice, i.v. cisplatin caused proteinuria (1 g l-1), glycosuria (16.7 mM) and decreased GFR at 4 days, and histological kidney damage with onset at 6 days. In contrast, mice treated with i.v. carboplatin or p.o. ammine/amine Pt(IV) dicarboxylates had urinary glucose, urinary protein, GFR and kidney histology within the control range. In rats, i.v. cisplatin caused 5-fold elevations in plasma creatinine (188 +/- 33 microM) and urea (30.4 +/- 8.9 mM), a 10-fold fall in creatinine clearance (0.54 +/- 0.31 ml min-1 kg-1), a 25-fold elevation in urine/plasma glucose concentration ratio (3.28 +/- 0.17), a 20% increase in kidney weight (7.9 +/- 0.56 mg gm-1 body weight) and extensive histological damage 4 days after treatment. In contrast, i.v. carboplatin and p.o. JM216 (the lead compound of this series) caused neither abnormalities in renal function nor histological damage in rats. The nephrotoxicity of single MTD treatments of p.o. ammine/amine Pt(IV) dicarboxylate complexes appears less than i.v. cisplatin and comparable to i.v. carboplatin.
McKeage
M J
MJ
Drug Development Section, Institute of Cancer Research, Sutton, Surrey.
Morgan
S E
SE
Boxall
F E
FE
Murrer
B A
BA
Hard
G C
GC
Harrap
K R
KR
D000284:Administration, Oral; D000818:Animals; D016190:Carboplatin / Q000633:toxicity; D002945:Cisplatin / Q000633:toxicity; D005260:Female; D007668:Kidney / Q000187:drug effects*; D007677:Kidney Function Tests; D051379:Mice; D008807:Mice, Inbred BALB C; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
D009944:Organoplatinum Compounds; D016190:Carboplatin; D002945:Cisplatin