Validation and use of microdialysis for determination of pharmacokinetic properties of the chemotherapeutic agent mitomycin C - an experimental study.
BACKGROUND
Mitomycin C is a chemotherapeutic agent used in the treatment of peritoneal surface malignancies, administered as hyperthermic intraperitoneal chemotherapy after cytoreductive surgery. Pharmacokinetic studies have been based on analyses of blood, urine and abdominal perfusate, but actual tissue concentrations of the drug have never been determined. Microdialysis is an established method for continuous monitoring of low-molecular substances in tissues, and in the present study microdialysis of mitomycin C was studied in vitro and in vivo.


METHODS
Using in vitro microdialysis, relative recovery was determined when varying drug concentration, temperature and perfusion flow rate. In vivo microdialysis was performed in rats to verify long-term stability of relative recovery in four compartments (vein, peritoneum, extraperitoneal space and hind leg muscle). Subsequently, intravenous and intraperitoneal bolus infusion experiments were performed and pharmacokinetic parameters were calculated.


RESULTS
In vitro, compatibility of mitomycin C and microdialysis equipment was demonstrated, and relative recovery was stable over an adequate concentration range, moderately increased by raising medium temperature and increased when flow rate was reduced, all according to theory. In vivo, stable relative recovery was observed over seven hours. Mitomycin C exhibited fast and even distribution in rat tissues, and equal bioavailability was achieved by intravenous and intraperitoneal infusion. The half-life of mitomycin C calculated after intravenous infusion was 40 minutes.


CONCLUSIONS
Mitomycin C concentration can be reliable monitored in vivo using microdialysis, suggesting that this technique can be used in pharmacokinetic studies of this drug during hyperthermic intraperitoneal chemotherapy.
Sørensen
Olaf
O
Department of Surgical Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Montebello, 0310 Oslo, Norway. olaf.sorensen@radiumhospitalet.no
Andersen
Anders
A
Olsen
Harald
H
Alexandr
Kristian
K
Ekstrøm
Per Olaf
PO
Giercksky
Karl-Erik
KE
Flatmark
Kjersti
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D007274:Injections, Intraperitoneal; D008297:Male; D017551:Microdialysis; D016685:Mitomycin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D010537:Peritoneum / Q000187:drug effects*; D051381:Rats; D011923:Rats, Nude; D014018:Tissue Distribution
D000903:Antibiotics, Antineoplastic; D016685:Mitomycin
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