Doxorubicin levels in the serum and ascites of patients with ovarian cancer W.H. Gotlieb a, * , I. Bruchim a , G. Ben-Baruch b , B. Davidson c , A. Zeltser b , A. Andersen d , H. Olsen d a Division of Gynecologic Oncology, Jewish General Hospital, McGill University, 3755 Cote Ste Catherine, Suite A-632, Montreal, QC H3T 1E2, Canada b Department of Gynecologic Oncology, Sheba Medical Center, Tel Aviv University, Tel Hashomer, Israel c Department of Pathology, The Norwegian Radium Hospital, University of Oslo, Montebello, N-0310 Oslo, Norway d Clinical Pharmacology Section, Central Laboratory, The Norwegian Radium Hospital HF, N-0310 Oslo, Norway Accepted 8 November 2006 Available online 15 December 2006 Abstract Aims: To investigate the diffusion and accumulation of doxorubicin metabolites in the ascites of patients with ovarian cancer following intravenous injection, as a model for intraperitoneal accumulation of drugs. Methods: The concentrations of doxorubicin and its metabolites [Doxorubicinol (Dox-ol), 7-deoxydoxorubicinolone (7d-Dox-ol-on) and 7-deoxydoxorubicinone (7d-Dox-on)] were measured using high-performance liquid chromatography in the serum and in the ascites of seven patients with recurrent ovarian carcinoma suffering from symptomatic ascites and treated with intravenous doxorubicin. Results: Doxorubicin metabolites accumulated in the peritoneal cavity. The concentrations of the doxorubicin metabolites were initially higher in the serum compared to the ascitic fluid, but following several hours the doxorubicin metabolites became higher in the ascites, and remained detectable in the ascites for up to 168 h, long after disappearance from the serum. Conclusions: Doxorubicin metabolites accumulate in the ascites and are cleared more slowly from the peritoneal compartment than from the serum. Accumulation in the peritoneal cavity with prolonged half-life should be considered when administering medication in patients with ascites. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Ovarian cancer; Ascites; Doxorubicin; Chemotherapy; Paracentesis; Toxicity Introduction Effectiveness and toxicities associated with drugs are partly related to their distribution in the various body com- partments. Following the recent publication in the New England Journal of Medicine 1 concerning the improved survival of patients with ovarian cancer using intraperi- toneal chemotherapy, much attention has focused on the importance of the intraperitoneal compartment. In this con- text we aimed to evaluate the potential diffusion and accu- mulation of drugs in the peritoneal cavity following intravenous administration. We analyzed patients with recurrent ovarian cancer, treated with intravenous doxoru- bicin, who suffered from symptomatic ascites and were scheduled for therapeutic paracentesis. Anthracyclines have been in clinical practice since the 1960s, and represent one of the most commonly used classes of anticancer drugs. 2,3 Doxorubicin is highly protein bound and does not cross the blood-brain barrier. In vivo, doxorubicin is extensively metabolized and excreted in the bile. 3 At least five biotransformation products have been identified. In this work, we report on the shift in concentrations of doxorubicin and its metabolites in the serum and intraperito- neal cavity over time following intravenous administration. Material and methods Patients and treatment Seven consecutive patients with recurrent ovarian carci- noma, who underwent paracentesis to relieve symptomatic ascites and received treatment with intravenous doxorubicin, * Corresponding author. Tel.: þ1 514 340 8222x3114; fax: þ1 514 340 8619. E-mail address: walter.gotlieb@mcgill.ca (W.H. Gotlieb). 0748-7983/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2006.11.006 EJSO 33 (2007) 213e215 www.ejso.com