Single-dose pharmacokinetics of a novel oral platinum cytostatic drug ([OC-6-43]-bis[acetato][1-adamantylamine]amminedichloroplatinum [IV]) in pigs.
The pharmacokinetics of total platinum (Pt) were investigated after a single oral dose of (OC-6-43-bis(acetato)(1-adamantylamine)amminedichloroplatinum (IV) (LA-12). A dose of 3 mg/kg (n = 3) and 30 mg/kg (n = 3) was given to two parallel groups of pigs (n = three each). Pt was measured in the blood, urine and feces by atomic absorption spectrometry. Blood was sampled at specified times until 240 h, urine was obtained through a catheter at 1-h intervals until 6 h, and feces were collected until 240 h after administration. LA-12 was rapidly absorbed, as indicated by a T(max) of total Pt within 0.5-1.5 h after administration. The mean (SEM) values for maximum plasma concentration (0.060 +/- 0.025 and 0.39 +/- 0.08 mg/l) and the area under the plasma concentration vs. time curve (12.6 +/- 5.6 and 36.3 +/- 2.0 mg.h/l) increased less than proportionally to the increase in the dose. The mean (SEM) Pt urinary excretion determined over a 6-h postdose period achieved only 1.9% and 0.8% of the administered doses, respectively. Within 2 h after dosing, the renal clearance of total Pt was approximately 2-fold higher than that of creatinine (CL(cr)). Thereafter, it steadily dropped and in the last collection interval (5-6 h postdose) its value was 50% less than CL(cr). Platinum recoveries in feces over 10 days after dosing reached 0.4% and 2.6% of the administered dose, respectively. This finding indicates that the extent of absorption of both doses was high. There were no changes in results of hematology and clinical biochemistry tests.
Cermanova
J
J
Department of Pharmacology, Charles University, Faculty of Medicine, 500 36, Hrádec Kralové, Prague, The Czech Republic.
Chladek
J
J
Soval
P
P
Kroutil
A
A
Semerad
M
M
Berankova
Z
Z
Siroky
P
P
Surova
I
I
D000284:Administration, Oral; D000547:Amantadine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical / Q000379:methods / Q000639:trends; D018153:Czech Republic; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005243:Feces / Q000737:chemistry; D005260:Female; D006207:Half-Life; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D010984:Platinum / Q000097:blood / Q000652:urine; D015203:Reproducibility of Results; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C482801:bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV); D010984:Platinum; D000547:Amantadine