Different Tissue Distribution of Paclitaxel With Intravenous and Intraperitoneal Administration

https://doi.org/10.1016/j.jss.2008.06.049Get rights and content

Purpose

Paclitaxel is considered to be suitable for disseminated cancer in the peritoneal cavity because of its high molecular weight and lipophilic characteristics. However, the difference in pharmacokinetics of paclitaxel after intraperitoneal (i.p.) and intravenous (i.v.) administration is not fully defined. Here, we investigated the tissue concentration of paclitaxel in various organs at various time points after i.p. or i.v. administration.

Methods

Paclitaxel (5 mg/kg) was administrated in an ear vein or in the abdominal cavity of rabbits. At 0.5, 6, 24, and 48 h after administration, the rabbits were sacrificed, and organs as well as peripheral blood were harvested. The serum and tissue concentrations of paclitaxel were measured by HPLC procedure.

Result

The concentration of paclitaxel was high in the i.v. group at 0.5 h, whereas it was significantly higher in the i.p. group at 6 and 24 h. The AUC (area under the curve) was markedly higher in the omentum, mesenteric lymph nodes as well as ovary and stomach in the i.p. group.

Conclusion

Compared with i.v. administration, paclitaxel concentration was maintained at a high level in the whole body by i.p. administration. Repeated i.p. paclitaxel can produce more marked clinical effects than i.v. administration for metastatic lymph nodes and primary lesions as well as peritoneal dissemination.

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.

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