A comparative study of pharmacokinetics, urinary excretion and tissue distribution of platinum in rats following a single-dose oral administration of two platinum(IV) complexes LA-12 (OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) and satraplatin (OC-6-43)-bis(acetato)amminedichloro(cyclohexylamine)platinum(IV).
OBJECTIVE
This study compared the pharmacokinetics, tissue distribution, and urinary excretion of platinum in rats after single oral doses of LA-12 and satraplatin.


METHODS
Both platinum derivatives were administered to male Wistar rats as suspensions in methylcellulose at four equimolar doses within the range of 37.5-300 mg LA-12/kg body weight. Blood sampling was performed until 72 h, and plasma and plasma ultrafiltrate were separated. Moreover, urine was collected until 72 h, and kidney and liver tissue samples were obtained at several times after administration. Platinum was measured by atomic absorption spectrometry. The pharmacokinetics of platinum was analyzed by population modelling and post hoc Bayesian estimation as well as using non-compartmental pharmacokinetic analysis of the mean concentration-time curves.


RESULTS
Platinum was detected in all plasma and ultrafiltrate samples 15 min after oral administration of both compounds and peaked between 3-4 h and 1-3 h, respectively. Similar for LA-12 and satraplatin, the C (max) and AUC values of plasma and ultrafiltrate platinum increased less than in proportion to dose. The mean C (max) and AUC values of plasma platinum observed after administration of LA-12 were from 0.84 to 2.5 mg/l and from 20.2 to 75.9 mg h/l. For ultrafiltrate platinum, the corresponding ranges were 0.16-0.78 mg/l and 0.63-1.8 mg h/l, respectively. The AUC of plasma platinum was higher after satraplatin (P < 0.001). However, administration of LA-12 resulted in significantly higher AUC values of ultrafiltrate platinum after the doses of 150 mg and 300 mg/kg (P < 0.01), respectively, and the C (max) values were significantly higher starting from the dose of 75 mg/kg LA-12 and upward (P < 0.01). Cumulative 72-h urinary recovery of platinum dose was below 5% for both compounds, and it decreased with the dose of satraplatin (P < 0.01), while a numerical decrease was observed after administration of LA-12 that did not reach statistical significance (P = 0.41). The renal clearance of free platinum was similar regardless of the dose and compound administered. Platinum concentrations in the liver homogenate exceeded those in the kidney. Distribution of platinum to tissues was higher after LA-12 compared to satraplatin. The difference in kidney platinum increased with dose and was twofold after 350 mg/kg LA-12. Liver platinum was twofold higher after LA-12 across all four doses.


CONCLUSIONS
In conclusion, this first comparative pharmacokinetic study with LA-12 and satraplatin shows that characteristics of platinum exposure evaluated in the plasma, plasma ultrafiltrate and kidney and liver tissues increase less than in proportion to dose following a single-dose administration of 37.5-300 mg/kg to Wistar rats. These findings together with the dose-related elevation in the pharmacokinetic characteristics V/F and CL/F of platinum and ultrafiltrate platinum as well as a drop in platinum urinary recovery are consistent with a dose-related decrease in the extent of oral bioavailability most likely due to saturable intestinal absorption.
Sova
Petr
P
R&D, PLIVA-Lachema as, Brno, Czech Republic.
Mistr
Adolf
A
Kroutil
Ales
A
Semerád
Martin
M
Chlubnová
Hana
H
Hrusková
Veronika
V
Chládková
Jirina
J
Chládek
Jaroslav
J
D000284:Administration, Oral; D000547:Amantadine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000652:urine; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D001499:Bayes Theorem; D008297:Male; D008954:Models, Biological; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C482801:bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV); C081294:satraplatin; D000547:Amantadine