Pharmacokinetic and pharmacodynamic analysis of platinum after combined treatment of cisplatin and procainamide hydrochloride in mice bearing P388 leukemia.
BACKGROUND
Our previous studies showed that procainamide hydrochloride may be an important modulator of cisplatin toxicity and antitumour activity. This study was performed in order to investigate if procainamide hydrochloride may influence the therapeutic index of cisplatin by inducing modifications of its pharmacokinetics and pharmacodymanics in vivo.


METHODS
The pharmacokinetic profile of cisplatin administered either in the presence or absence of procainamide hydrochloride was investigated in BDF1 female mice bearing 6-day P388 leukemia. Procainamide hydrochloride was administered i.v. at the dose of 50 mg/kg, immediately before cisplatin which, in turn, was administered i.p. at the dose of 8 mg/kg.


RESULTS
The combined administration of the antiarrhythmic drug and cisplatin caused significant differences in the pharmacokinetic profiles of Pt in plasma, ascites fluid and tissues. Filterable Pt was significantly increased both in plasma and ascites fluid in animals given the combined treatment. Similarly, a small increase was also found for total plasma Pt. These differences caused some changes of the pharmacokinetic parameters of filterable (plasma: AUC0-1 h = +16%, t1/2 alpha = +29%, t1/2b = +14%, K2p = -32%; ascites fluid: AUC0-1 h = +23%, t1/2 alpha = +78%, t1/2 beta = -49%, and total Pt (plasma: AUC0-1 h = +19%, t1/2 alpha = +27%, t1/2 beta = -22%; ascites fluid: AUC0-1 h = +6%, AUC0-infinity = +43%, t1/2 alpha = +30%). The analysis of tissue Pt content showed the general increase of Pt concentration in the main organs of animals treated with cisplatin and procainamide hydrochloride, with AUC0-24 h increased by 95%, 22%, 90% and 28% in kidney, liver, spleen and lung, respectively. The analysis of binding of Pt to DNA and percent interstrand cross-links (%ISCL) in P388 tumour cells showed that the % ISCL (10.44 +/- 3.81% vs. 3.51 +/- 0.01%) and the efficiency of ISCL formation (0.51 +/- 0.14 vs. 0.17 +/- 0.02 %ISCL.microgram DNA/pg Pt) were significantly greater when cisplatin was administered in association with procainamide hydrochloride.


CONCLUSIONS
Our results show that procainamide hydrochloride may alter the pharmacodynamics and the pharmacokinetics and distribution of Pt in tumored mice treated with cisplatin.
Vannozzi
Maria O
MO
Istituto Nazionale per la Ricerca sul Cancro, Unità di Farmacologia Tossicologica, Lgo R. Benzi, 10, 16132 Genova.
Ottone
Massimo
M
Mariggiò
Maria A
MA
Cafaggi
Sergio
S
Parodi
Brunella
B
Cilli
Michele
M
Lindup
Edward
E
Viale
Maurizio
M
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D019540:Area Under Curve; D001202:Ascitic Fluid / Q000737:chemistry; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000517:prevention & control; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D003432:Cross-Linking Reagents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D018736:DNA Adducts; D004273:DNA, Neoplasm / Q000737:chemistry / Q000187:drug effects; D005260:Female; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control; D007941:Leukemia P388 / Q000188:drug therapy*; D051379:Mice; D009928:Organ Specificity; D010984:Platinum / Q000032:analysis* / Q000493:pharmacokinetics; D011342:Procainamide / Q000008:administration & dosage / Q000494:pharmacology*; D014018:Tissue Distribution
D003432:Cross-Linking Reagents; D018736:DNA Adducts; D004273:DNA, Neoplasm; D010984:Platinum; D011342:Procainamide; D002945:Cisplatin