Effect of hyperthermia on cisplatin and carboplatin disposition in the isolated, perfused tumour and skin flap.
The effect of hyperthermia on the disposition of platinum (Pt) from cisplatin (CDDP) and carboplatin (CBDCA) in the isolated, perfused tumour and skin flap (IPTSF) was evaluated. Flaps (n = 4/treatment) were perfused with 3.0 micrograms CDDP or 15 micrograms CBDCA/ml perfusion medium at a rate of 1 ml/min for 3 h. Two-hour (CDDP experiments) or 3 h (CBDCA experiments) washout phases were then performed. The disposition kinetics of free Pt were characterized using a four-compartment, physiologically relevant, pharmacokinetic model. Hyperthermia (HT) may have enhanced the mobility of Pt but it did not increase total Pt mass in the tissue compartments in CDDP experiments. Conversely, HT significantly increased Pt mass in the fixed, non-tumour tissue compartment (p < 0.05) in CBDCA experiments. While a similar trend was noted in the fixed, tumour tissue compartment of CBDCA-treated flaps, the difference was not significant (p = 0.17). Total tissue Pt mass was significantly greater in CDDP compared with CBDCA experiments (p < 0.05). In conclusion, HT alters the disposition of Pt from CDDP and CBDCA under conditions of constant rate infusion. Further characterization of factors influencing drug disposition to non-tumour and tumour tissues can be systematically accomplished using the IPTSF.
Vaden
S L
SL
Cutaneous Pharmacology and Toxicology Center, College of Veterinary Medicine, North Carolina State University, Raleigh 27606.
Page
R L
RL
Williams
P L
PL
Riviere
J E
JE
D000818:Animals; D001833:Body Temperature Regulation; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003131:Combined Modality Therapy; D006979:Hyperthermia, Induced; D066298:In Vitro Techniques; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000503:physiopathology / Q000628:therapy*; D010477:Perfusion; D010984:Platinum / Q000493:pharmacokinetics; D013524:Surgical Flaps; D013552:Swine
D010984:Platinum; D016190:Carboplatin; D002945:Cisplatin