Biodistribution analysis of cisplatin in liposomal form in animals with cisplatin-resistant and cisplatin-sensitive carcinoma.
OBJECTIVE
To analyze the relation between pharmacokinetics of cisplatin in liposomal form and antitumor efficacy toward cisplatin-resistant and cisplatin-sensitive variants of Guerin carcinoma.


METHODS
Concentration of platinum was measured by atomic absorption spectrophotometry (C115M1 "Selmi", Ukraine). Elimination constant was calculated based on the dynamics of cisplatin concentration in time period between 1 h to 24 h using nonlinear regression analysis. Area under curve (AUC24) was calculated by the trapezium method.


RESULTS
It was shown that for liposomal form of cisplatin (LCp) AUC24 in tumor practically didn't depend on the level of the tumor sensitivity, while in animals with the resistant variant (CpRGC), AUC24 for free cisplatin (FCp) decreased by 70% less (p < 0.001) as compared to the sensitive tumor strain (CpSGC). Significant decrease of elimination constant of LCp compared to FCp in blood serum of rats bearing either CpRGC or CpSGC tumors favors cisplatin accumulation in tumor tissues with low vascularization level. The dynamics of cisplatin concentration in CpRGC variant was characterized by 90% higher level in 24 h after administration of LCp as compared to FCp (p < 0.05). This fact may explain increased antitumor efficacy of LCp compared to FCp toward CpRGC variant. In the study of kidney function, AUC24 index for LCp was by 68.6% (p < 0.01) and 50.7% (p < 0.05) lower than AUC24 index for FCp in rats with CpRGC and CpSGC variants, respectively. No significant differences have been found in biodistribution of cisplatin in both pharmaceutical forms in liver and lung in CpRGC- or CpSGC-bearing rats.


CONCLUSIONS
The results suggest that cisplatin in liposomal form possesses higher specificity of antitumor action than free cisplatin.
Nosko
M M
MM
R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv 03022, Ukraine. mykhailo.nosko@gmail.com
Pivnyuk
V M
VM
Solyanik
G I
GI
Kulik
G I
GI
Todor
I N
IN
Momot
V Ya
VY
Melnikov
O R
OR
Ponomareva
O V
OV
Chekhun
V F
VF
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001682:Biological Availability; D002277:Carcinoma / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D008081:Liposomes; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects
D000970:Antineoplastic Agents; D008081:Liposomes; D002945:Cisplatin