Pharmacokinetics and pharmacodynamics of cisplatin after intraoperative hyperthermic intraperitoneal chemoperfusion (HIPEC).
BACKGROUND
HIPEC is a new treatment modality for abdominal cancers that combines cytoreductive surgery with Hyperthermic, Intraoperative Peritoneal Chemotherapy, followed by systemic chemotherapy. A significant survival benefit has been shown for HIPEC compared with systemic therapy alone. However, it is not clear what is the contribution of i.p. drug delivery and what influence the mild hyperthermia has on the uptake of cisplatin in abdominal tumors.


METHODS
We used a peritoneal perfusion system in rats to compare the pharmacokinetics and pharmacodynamics of cisplatin, after normothermic (37 degrees C/90 minutes) and hyperthermic (40 degrees C/90 minutes) intra-peritoneal perfusion, with an i.p. bolus injection.


RESULTS
Hyperthermic perfusion with 15 micrograms/ml (in 200 ml) cisplatin gave equivalent plasma drug levels to a maximum tolerated dose (MTD) i.p. bolus injection of 4 mg/kg (36 micrograms/ml in 20 ml). The drug concentration in small (1-5 mm) intra-peritoneal tumors was also comparable for both these treatments, and for normothermic perfusion.


CONCLUSIONS
Mild hyperthermic perfusion with cisplatin (40 degrees C/90 minutes) did not improve drug uptake in small intra-peritoneal tumors, relative to normothermic perfusion or i.p. bolus injection.
Zeamari
S
S
Department of Experimental Therapy, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Floot
B
B
van der Vange
N
N
Stewart
F A
FA
D000042:Absorption; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002945:Cisplatin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000473:pathology; D003131:Combined Modality Therapy; D005260:Female; D006979:Hyperthermia, Induced; D007263:Infusions, Parenteral; D007274:Injections, Intraperitoneal; D007432:Intraoperative Period; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D020714:Maximum Tolerated Dose; D009368:Neoplasm Transplantation; D010477:Perfusion; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000556:secondary / Q000628:therapy*; D010537:Peritoneum / Q000378:metabolism; D051381:Rats; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D002945:Cisplatin