EFFECTS OF INTRAABDOMINAL PRESSURE ON PHARMACOKINETICS AND TISSUE DISTRIBUTION OF DOXORUBICIN AFTER INTRAPERITONEAL ADMINISTRATION

Increased hydrostatic pressure in solid tumor nodules decreases the pe netration of chemotherapy into cancerous tissue. This is true for both i.v. and i.p. chemotherapy. The purpose of this study was to determin e the influence of increasing intra-abdominal pressures on the pharmac okinetics and tissue distribution of doxorubicin administered i.p. Fou r groups of 10 Sprague Dawley rats were given i.p. doxorubicin (4 mg/k g) during 60 min combined with no pressure (control), 10, 20 and 30 mm Hg pressures. During the course of i.p. chemotherapy, peritoneal flui d and blood were sampled. Two other groups of 10 rats received the sam e dose of i.p. doxorubicin during 10 min combined with no pressure and 30 mm Hg pressure. At the end of experiments animals were sacrificed and tissue samples were collected. Doxorubicin concentrations in perit oneal fluid, plasma and tissues were determined by HPLC. Pharmacokinet ic studies showed that increased intraabdominal pressures of 10, 20 an d 30 mm Hg did not alter peritoneal fluid AUCs, the plasma AUCs and th e peak ratios of i.p. doxorubicin when compared to the control group ( no pressure). A subset analysis of high intra-abdominal pressure group s (20 and 30 mm Hg) versus control group showed statistically signific ant differences in peritoneal fluid AUCs, plasma AUCs and AUC (periton eal fluid/plasma) ratios. For all groups, the highest tissue concentra tions of doxorubicin were found in tissues associated with the parieta l peritoneum: the bladder, the abdominal wall and the diaphragm. After 10 min of i.p, chemotherapy, the group treated with 30 mm Hg pressure showed a significant increase of doxorubicin concentrations in these tissues as compared to the control group. This significant increase of tissue doxorubicin concentrations was not found after 60 min of press ure with i.p. chemotherapy; prolonged intra-abdominal pressure was ass ociated with a high incidence of intestinal ischemia. In conclusion, i ntra-abdominal pressure of 20 and 30 mm Hg significantly decreased the AUC ratios of i.p. doxorubicin but concomitantly increased tissue upt ake of doxorubicin in bladder, diaphragm and abdominal wall during the first 10 min of i.p. administration. These findings may have signific ance in the design of improved strategies to increase tissue concentra tions of chemotherapy delivered by an i.p. route.