Cis-diamminedichloroplatinum (II)-procaine pharmacokinetic interaction in mice bearing P388 leukemia.
The distribution and elimination kinetics of cis-diamminedichloroplatinum (II) (DDP) in female BDF1 mice bearing 6-day P388 leukemia were investigated in the presence and absence of procaine hydrochloride (P.HCl) exposure. DDP was administered as a single i.p. dose of 8 mg/kg in a 0.9% NaCl solution 6 days after tumor inoculum. P.HCl was administered as a single i.v. dose of 40 mg/kg immediately after DDP. The combined treatment with P.HCl produced marked changes in the plasma concentration-time profile of Pt. The unbound fraction of Pt was significantly increased both in the ascites fluid and plasma following DDP + P.HCl administration. P.HCl treatment induced a significant reduction (P < 0.01) in the rate constant of the protein-bound of Pt in plasma of tumored mice. Urinary excretion of Pt was unaffected by P.HCl, and there was no significant P.HCl-induced modification in the concentrations of Pt in the P388 leukemic cells. A statistically significant reduction of kidney and spleen Pt content was observed in female mice exposed to a dose of 8 mg/kg DDP + P.HCl. A similar reduction was observed in kidneys and testes of tumored mice receiving 16 mg/kg DDP along with 40 mg/kg P.HCl, which also showed lower renal and testicular cisplatin-DNA adducts after DDP + P.HCl than after DDP treatment. Potential explanations for the ability of P.HCl to interfere with the pharmacokinetics and biodistribution of DDP are discussed.
Esposito
M
M
Servizio di Farmacologia Tossicologica, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Vannozzi
M O
MO
Viale
M
M
Pellecchia
C
C
Merlo
F
F
Cadoni
A
A
Cafaggi
S
S
Parodi
B
B
Lerza
R
R
Poirier
M C
MC
D000818:Animals; D002945:Cisplatin / Q000032:analysis / Q000493:pharmacokinetics*; D004247:DNA / Q000032:analysis; D018736:DNA Adducts; D004347:Drug Interactions; D005260:Female; D007668:Kidney / Q000378:metabolism; D007941:Leukemia P388 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011343:Procaine / Q000493:pharmacokinetics*; D013154:Spleen / Q000378:metabolism; D013737:Testis / Q000378:metabolism; D014018:Tissue Distribution
D018736:DNA Adducts; C057270:cisplatin-DNA adduct; D011343:Procaine; D004247:DNA; D002945:Cisplatin