Pharmacokinetic analysis of drug disposition after intratumoral injection in a tissue-isolated tumor perfusion system.
OBJECTIVE
The purpose of this study was to establish an experimental system for evaluation of the intratumoral behavior of drugs after intratumoral injection using perfused tissue-isolated tumor preparations of Walker 256 carcinoma (3.46-9.73g, n = 16).


METHODS
We quantified the recovery of Phenol Red (model drug) in the tumor, leakage from the tumor surface and the venous outflow after intratumoral injection using perfused tissue-isolated tumors, and analyzed venous appearance curves based on a pharmacokinetic model in which the tumor tissue was assumed to be divided into two compartments, i.e., well- and poorly-perfused regions.


RESULTS
In small tumors (Type 1, 5.42 +/- 0.39 g), the drug appeared immediately in the venous outflow, and the amount remaining in the tumor tissue at 2 hr after injection was small. In contrast the venous appearance rate reached a significantly lower peak a few minutes after injection, and a large amount of injected drug remained in some large tumors (Type 2.8.17 +/- 0.51 g). Pharmacokinetic analysis revealed that there was a correlation between tumor weight and the rate constants of transfer from the poorly-perfused region to the well-perfused region, and between the rate constants of transfer from the well-perfused region to the venous outflow and dosing ratios into the well-perfused region.


CONCLUSIONS
An experimental system and analytical method were established for the evaluation of the intratumoral behavior of drugs after intratumoral injection using a tissue-isolated tumor perfusion system. This experimental system will be useful in analyzing the antitumor drug disposition after intratumoral injection.
Saikawa
A
A
Department of Drug Delivery Research, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Nomura
T
T
Yamashita
F
F
Takakura
Y
Y
Sezaki
H
H
Hashida
M
M
D000818:Animals; D002279:Carcinoma 256, Walker / Q000098:blood supply / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D005070:Evans Blue / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D015552:Injections, Intralesional; D010477:Perfusion; D010637:Phenolsulfonphthalein / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000493:pharmacokinetics; D014018:Tissue Distribution
D012710:Serum Albumin, Bovine; D005070:Evans Blue; D010637:Phenolsulfonphthalein