Intraperitoneal administration

A pro-drug approach for improving the pharmacokinetics of zanamivir has recently shown some promise. The alkoxyalkyl ester 23 of zanamivir, with long alkyl chains chosen to counteract the high hydrophUicity of the molecule, was reported to show significant protective effects against influenza (HlNl) infection in mice upon oral or intraperitoneal administration (Liu et al. 2007). 

Intraperitoneal administration of chemotherapeutic agents has been used for many years as a way of increasing the delivery of drugs to tumors (e.g., ovarian carcinoma) located in the peritoneal cavity (Markman, 1986 Howell and Zimra, 1988). Cisplatin (Casper et al., 1983 Markman et al., 1985), cytosine arabinoside (Ara-C) (King et al., 1984 Markman et al., 1985, 1986), and bleomycin (Markman et al., 1986) are examples of intraperitoneally administered drugs which were already successfully applied in clinical settings. 

Several studies have been performed in order to investigate the effect of liposomal size (Hirano and Hunt, 1985), lipid composition (Senior and Gregoriadis, 1982 Hirano et al., 1985), and lipid dose (Ellens et al., 1983, Kim et al., 1987) on the fate of liposomes after intraperitoneal administration. In the size range studied (0.048-0.72 Min), no size-dependent absorption could be expected (Hirano and Hunt, 1985). Particles larger than 22.5 pm are not expected to enter the lymphatic capillaries (Allen, 1956). After intraperitoneal administration of multivesicular liposomes (19 + 7 ym), Kim and Howell (1987a) and Kim et al. (1987) showed that liposomal entrapment of Ara-C prolongs the half-Ufe of the drug in the peritoneal... 

Kim et al. (1987) showed that the prolonged retention time of Ara-C in the peritoneal cavity after intraperitoneal administration of the drug in liposomal form as discussed above resulted in better therapeutic effects on intraperitoneally inoculated L1210 cells, as compared to the free drug. The activity of intraperitoneally administered cDDP on Ehrlich ascites carcinoma in mice was increased after encapsulation in neutral liposomes (Sur et al., 1983). The in vivo studies revealed improved antitumor activity and a lower toxicity sifter administration of cDDP liposomes compared to free drug. 

Hirano, K., and Hunt, C. A. (1985). Lymphatic transport of liposome-encapsulated agents Effects of liposome size following intraperitoneal administration, J. Pharm. Sci., 74, 915-921. 

Parker, R. J., Hartman, K. D., and Sieber, S. M. (1981b). Lymphatic absorbtion and tissue disposition of liposome-entrapped [1 CJadriamycin following intraperitoneal administration, Cancer Res., 41, 1311-1317. 

The second ester bond in diisopropyl methylphosphonate is more stable to hydrolysis than the first, and IMPA undergoes relatively little decomposition to MPA. After intraperitoneal administration of 160 mg/kg [32P]-labeled IMPA to a single male rat, the IMPA was excreted unmodified in the urine with no evidence of further metabolism (Hoskin 1956). 

Within 8 days of an intraperitoneal dose of 0.66 mL/kg tritiated mineral oil to rats, 11% of administered radioactivity was excreted in the feces, predominately in the form of mineral oil (95%) (Ebert et al. 1966). Urine during the same time frame after intraperitoneal administration contained about 8% of the administered radioactivity, but in chemical forms other than mineral oil. The detection of radioactivity in the feces after intraperitoneal administration suggests that significant biliary excretion of absorbed mineral oil can occur. 

Fig. 14 Mitomycin concentration of ascites in rates bearing AH-130 after intraperitoneal administration (dose 2 mg/kg in saline solution open circles, mitomycin adsorbed on activated carbon solid circles, free mitomycin n — 5). (From Ref. 178.)...

Table 13 Mitomycin Concentration (mg/g) in Tumors and Organs After Intraperitoneal Administration of Mitomycin-Activated Carbon and Mitomycin in Saline Solutions (dose 2 mg/kg)... 

Nontoxic responses were reported by Chiaretti et al. [90], who investigated the pathological effects of MWNTs on the parenchymal tissues after intraperitoneal administration. Only high doses of MWNTs (20 and 40 mg kg-1) caused death of animals in the first day (20 and 33%, respectively), whereas doses of 5 and 10 mg kg-1 had no effect after 7 days. In addition, repeated administration of 5 mg kg-1 doses did not cause any lesion in the abdominal cavity or in the pleural and pericardial cavities. Only a small irritation was observed at the injection point. It should be emphasized that this study did not address the carcinogenicity risk associated with CNT exposure,... 

MWNTs Not specified (Mitsui) p53 (+/-) mice Intraperitoneal administration 175 d Carcinogenic effect [88]... 

Araki E, Ishikawa M, Iigo M et al. Relationship between development of diarrhea and the concentration of SN-38, an active metabolite of CPT-11, in the intestine and the blood plasma of athymic mice following intraperitoneal administration of CPT-11. Jpn J Cancer Res 1993 84 697-702. 

TABLE 3-7 Developmental Effects of Monomethylhydrazine in Rats Following Intraperitoneal Administration on Gestation Days 6-15... 

Ovarian hormones influence fluid intake by interaction with the brain renin-angiotensin system and it has been shown that gonadal steroids affect brain fluid-electrolyte balance by interactions with vasopressin. Both hyperos-molarity and increased intracranial pressure stimulate vasopressin release and intraperitoneal administration of vasopressin antagonists decrease brain volume. 

Thomas, P., K.N. Baer, and R.B. White. 1994. Isolation and characterization of metallothionein in the liver of the red-eared turtle (Trachemys scripta) following intraperitoneal administration of cadmium. Comp. Biochem. Physiol. 107C 221-226. 

Hood, R.D., G.C. Vedel-Macrander, M.J. Zaworotko, F.M. Tatum, and R.G. Meeks. 1987. Distribution, metabolism, and fetal uptake of pentavalent arsenic in pregnant mice following oral or intraperitoneal administration. Teratology 35 19-25. 

Turrin, N. P. et al. Pro-inflammatory and anti-inflammatory cytokine mRNA induction in the periphery and brain following intraperitoneal administration of bacterial lipopolysac-charide. Brain Res. Bul.l 54, 443, 2001. 

Pyrrolidation of proteins appears to be a necessary step in -hexane neurotoxicity, and the targets relevant to toxicity are thought to be neuronal axon proteins (Graham et al. 1995). However, w-hexane metabolites can pyrrolidate a variety of proteins at lysine residues, which upon oxidation can become crosslinked. Pyrrolidated proteins in rat hair have been measured after intraperitoneal administration of... 

Abou-Donia MB, Makkawy HA, Graham DG. 1982. The relative neurotoxicities of -hexane, methyl n-butyl ketone, 2,5-hexanediol, and 2,5-hexanedione following oral or intraperitoneal administration in hens. Toxicol Appl Pharmacol 62(3) 369-389. 

---