Disposition of anticancer drugs after bolus arterial administration in a tissue-isolated tumor perfusion system.
Disposition characteristics of various anticancer drugs in a tissue-isolated tumor preparation were studied in Walker 256 carcinosarcoma-bearing rats using an in situ single-pass vascular perfusion technique. Three anticancer drugs, 5-fluorouracil, mitomycin C, and Adriamycin, and two lipophilic prodrugs of mitomycin C were tested in the tumor preparation perfused with Tyrode's solution containing 4.7% bovine serum albumin. After bolus arterial injection of test drugs, their outflow concentration-time curves were analyzed based on statistical moment theory. In each tumor preparation, the injection of drug was paired with that of vascular reference substance, Evans' blue-labeled bovine serum albumin, and disposition parameters of the drug were corrected with those of vascular reference substance. From the mean transit time values of vascular reference substance, the average vascular volume of the tumor preparation was calculated to be 0.063 ml/g, which decreased with tumor growth. All drugs showed significant extraction by the tumor tissue, depending on their physicochemical properties. Distribution volumes of tested drugs were from 1.53 to 3.33 times larger than the vascular volume. Calculated intrinsic clearance values for the protein-unbound fractions increased as the lipophilicity of the drug increased. The potential increase in tumor uptake was observed in lipophilic prodrugs of mitomycin C. The present experimental system is thus suggested to be useful for analyzing drug disposition in tumor tissue.
Ohkouchi
K
K
Department of Basic Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Imoto
H
H
Takakura
Y
Y
Hashida
M
M
Sezaki
H
H
D000818:Animals; D002279:Carcinoma 256, Walker / Q000098:blood supply / Q000378:metabolism*; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007261:Infusions, Intra-Arterial; D016685:Mitomycin; D008937:Mitomycins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains
D008937:Mitomycins; D011355:Prodrugs; D016685:Mitomycin; D004317:Doxorubicin; D005472:Fluorouracil