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Článek online

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)

Cancer chemotherapy and pharmacology. 2011 ; 67 (6) : 1247-56.

Cancer Chemother Pharmacol
ISSN 1432-0843
Medvik
Zdroj

PURPOSE: 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.

MeSH
amantadin aplikace a dávkování analogy a deriváty farmakokinetika moč MeSH
aplikace orální MeSH
Bayesova věta MeSH
biologické modely MeSH
krysa rodu rattus MeSH
organoplatinové sloučeniny aplikace a dávkování farmakokinetika moč MeSH
potkani Wistar MeSH
protinádorové látky aplikace a dávkování farmakokinetika moč MeSH
tkáňová distribuce MeSH
zvířata MeSH
Check Tag
krysa rodu rattus MeSH
mužské pohlaví MeSH
zvířata MeSH
Publikační typ
časopisecké články MeSH
srovnávací studie MeSH

Článek ve sborníku

Platinový derivát LA-12 vykazuje vyšší toxicitu než oxaliplatina u buněk kolorektálního karcinomu (HT-29)

Edukační sborník. 2006 ; () : 74-75.

ISBN 80-86793-06-0
Medvik
Zdroj

Klíčová slova
platinový derivát LA-12,
MeSH
buněčné linie MeSH
buňky HT-29 * cytologie účinky léků MeSH
cisplatina analogy a deriváty terapeutické užití toxicita MeSH
farmakologické účinky MeSH
farmakoterapie metody trendy využití MeSH
kolorektální nádory farmakoterapie MeSH
kultivační techniky MeSH
lékařská onkologie metody trendy MeSH
lidé MeSH
organoplatinové sloučeniny terapeutické užití toxicita MeSH
protinádorové látky * terapeutické užití toxicita MeSH
techniky in vitro MeSH
Check Tag
lidé MeSH

Článek

Comparative anti-tumor efficacy of two orally administered platinum(IV) drugs in nude mice bearing human tumor xenografts

Anticancer Drugs. 2006 ; 17 (2) : 201-206.

Medvik
Zdroj

The oral anti-tumor activity of a novel platinum(IV) complex, coded as LA-12, with a bulky adamantylamine ligand was evaluated and compared with another platinum(IV) complex satraplatin. The human carcinoma xenografts of colon HCT116, prostate PC3, and ovarian A2780 and A2780/cisR (resistant to cisplatin) were used to evaluate the in-vivo anti-tumor activity. The daily x 5 repeated dose regimen in equimolar doses of LA-12 and satraplatin, administered in 2 cycles, was selected for this evaluation. All doses of LA-12 and satraplatin were significantly effective in comparison with the control. The activities of LA-12 in all doses and all used tumor xenografts were higher than equimolar doses of satraplatin. The highest effect was reached with LA-12 at a dose of 60 mg/kg. The shapes of growth curves of ovarian carcinoma A2780 and its subline resistant to cisplatin after therapy with LA-12 were very similar. This shows that LA-12 is able to overcome resistance to cisplatin.