Validation and use of microdialysis for determination of pharmacokinetic properties of the chemotherapeutic agent mitomycin C - an experimental study

Olaf Sørensen,Per Olaf Ekstrøm,Harald Olsen,Anders Andersen,Kristian Alexandr,Kjersti Flatmark,Karl-Erik Giercksky

doi:10.1186/1471-2407-10-469

Olaf Sørensen, Per Olaf Ekstrøm + Show 5 more

Open Access

https://doi.org/10.1186/1471-2407-10-469

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Journal: BMC Cancer	Publication Date: Sep 1, 2010
Citations: 37	License type: cc-by

Affiliation: Oslo University Hospital, University of Oslo

Abstract

BackgroundMitomycin 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.MethodsUsing 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.ResultsIn 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.ConclusionsMitomycin 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.

Highlights

Mitomycin C is a chemotherapeutic agent used in the treatment of peritoneal surface malignancies, administered as hyperthermic intraperitoneal chemotherapy after cytoreductive surgery
The efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) has not been proven in randomized controlled trials, the use of this treatment strategy has in recent years been extended to include selected patients with peritoneal carcinomatosis from more aggressive malignancies, mainly colorectal cancer [11,12]
Pharmacologic studies of MMC during HIPEC have hitherto been based on concentration analysis of blood, urine and abdominal perfusate collected during the procedure, but actual tissue concentrations have never been measured [13,14,15,16]

Summary

Introduction

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. As long as the disease is confined to the abdominal cavity, local administration of MMC in the form of HIPEC is an attractive principle, since high intraabdominal drug concentration is achieved relative to systemic absorption, which is the main dose-limiting factor. Pharmacologic studies of MMC during HIPEC have hitherto been based on concentration analysis of blood, urine and abdominal perfusate collected during the procedure, but actual tissue concentrations have never been measured [13,14,15,16]

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