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.
Department of Drug Delivery Research, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
A
A
Saikawa
T
T
Nomura
F
F
Yamashita
Y
Y
Takakura
H
H
Sezaki
M
M
Hashida
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