Different Tissue Distribution of Paclitaxel With Intravenous and Intraperitoneal Administration
Introduction
Paclitaxel was originally isolated from the tree Taxus brevifolia and elicits potent antitumor effects by stabilizing microtubules 1, 2. Many clinical trials have suggested the effectiveness of paclitaxel for a variety of cancers such as breast, ovarian, lung, head and neck, and stomach 3, 4, 5, 6, 7. In particular, intraperitoneal (i.p.) administration of paclitaxel has been tried in ovarian cancer, showing remarkable clinical effects against ovarian cancer, especially with peritoneal metastases 8, 9, 10, 11, 12. Similar results have been reported with fewer side effects in peritoneal carcinomatosis of gastric carcinoma 13, 14. Since the peritoneal cavity is the principal site for metastases or recurrence in these malignancies, i.p. paclitaxel is considered to be one of the most reliable therapeutic strategies for peritoneal malignancy.
Previous pharmacokinetic studies have shown that intraperitoneally administrated paclitaxel is slowly absorbed through the peritoneal lining and remains in the peritoneal cavity at relatively high concentrations for a long period, presumably due to its aqueous insolubility and high molecular weight 13, 15, 16, 17, 18. In addition, recent studies have shown that plasma paclitaxel concentration after i.p. administration exceeded the effective dose until 24 h [19], and was maintained at a detectable level for a wk [20]. These data suggest the possibility that i.p. administration of paclitaxel may be effective for extraperitoneal lesions as well as intraperitoneal metastases.
The mechanisms of the absorption of paclitaxel from the peritoneal cavity have not been satisfactorily evaluated. Some reports have shown that direct penetration of paclitaxel into adjacent tissues is limited to a few mm, which is thought to be similar to that of other drugs 21, 22, 23, 24, 25, 26. This suggests that hydrophobic drugs such as paclitaxel may be absorbed via a different route from the abdominal cavity, causing a unique drug distribution after i.p. administration. In this study, therefore, we used a rabbit model and comparatively examined the time course of the concentration of paclitaxel in various organs after i.v. and i.p. administration.
Section snippets
Drug and Animals
Paclitaxel (taxol) was donated by Bristol-Myers Squibb Japan (Tokyo, Japan). Female white Japanese rabbits weighing 3.0 to 3.5 kg (Saitama Rabbitry, Saitama, Japan) were individually housed and allowed free access to food and water.
Experimental Design
The rabbits were anesthetized with an intramuscular injection of a mixture of ketamine (50 mg/kg) and xylazine (2.5 mg/kg), and underwent laparotomy. A 16-gauge catheter for administration of drug was inserted through the abdominal incision. After administration, the
Serum Concentration of Paclitaxel
Serum concentration of paclitaxel showed a rapid increase during the first h after i.v. administration, and quickly decreased to below the effective dose level by 24 h (Fig. 1). In comparison, when paclitaxel was administrated via the i.p. route, the serum concentration gradually increased up to 3 h and did not decrease as rapidly as after i.v. administration. The serum concentration was almost identical at 1 h, and that in the i.p. group exceeded that in the i.v. group from 3 to 24 h after
Discussion
The present study clearly demonstrated that the concentration of paclitaxel was systemically maintained at a relatively higher level in the i.p. group than in the i.v. group at least until 24 h after administration. In particular, the tissue concentration in the omentum was constantly higher in the i.p. than in the i.v. group throughout the 24 h. Since the omentum is the most frequent anatomical site of peritoneal metastases in ovarian and gastric cancers, this finding supports the concept that
Acknowledgments
The authors thank Ms. Chieko Uchikawa and Mr. Noboru Sunaga for their excellent technical assistance.
References (31)
- et al.
Intraperitoneal chemotherapy with taxanes for ovarian cancer with peritoneal dissemination
Eur J Surg Oncol
(2006) - et al.
Intraperitoneal cisplatin-based chemotherapy versus intravenous cisplatin-based chemotherapy for Stage III optimally cytoreduced epithelial ovarian cancer
Int J Gynaecol Obstet
(2001) - et al.
Effect of intraperitoneal administration of docetaxel on peritoneal dissemination of gastric cancer
Cancer Lett
(2004) - et al.
A comparison of hetastarch and peritoneal dialysis solution for intraperitoneal chemotherapy delivery
Eur J Surg Oncol
(2003) - et al.
Rapid and sensitive determination of paclitaxel in mouse plasma by high-performance liquid chromatography
J Chromatogr B Biomed Sci Appl
(1999) Postinflammatory increase of absorption from peritoneal cavity into lymph nodes: Particulate and oily inocula
Exp Mol Pathol
(1985)- et al.
Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia
J Am Chem Soc
(1971) - et al.
Taxol: A novel investigational antimicrotubule agent
J Natl Cancer Inst
(1990) - et al.
Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer
J Natl Cancer Inst
(1991) - et al.
Phase II study and long-term follow-up of patients treated with taxol for advanced ovarian adenocarcinoma
J Clin Oncol
(1992)
Phase II study of taxol, merbarone, and piroxantrone in Stage IV non-small-cell lung cancer: The Eastern Cooperative Oncology Group Results
J Natl Cancer Inst
Final report of a Phase II evaluation of paclitaxel in patients with advanced squamous cell carcinoma of the head and neck: An Eastern Cooperative Oncology Group trial (PA390)
Cancer
Phase II study of taxol in patients with advanced gastric carcinoma
Cancer J Sci Am
Intraperitoneal cisplatin and paclitaxel in ovarian cancer
N Engl J Med
Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume Stage III ovarian carcinoma: An intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group
J Clin Oncol
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