Intraperitoneal drug administration toxicity

SAFETY PROFILE Confirmed carcinogen. US Food and Drug Administration recommends removal from laxative formulations. Moderately toxic by intraperitoneal route. Human systemic effects changes in urine composition, gastritis, nausea or vomiting. Used in medicine as a laxative in chemistry as an indicator. When heated to decomposition it emits acrid smoke and irritating fumes. 

In comparison with the intravenous route of administration the potential advantages of intraperitoneal therapy are the avoidance of high toxic drug plasma levels and an increased (local) exposure of tumors (cells) to anticancer drugs. Whether this increased exposure... 

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. 

Some pharmacokinetic properties of the commonly used amide local anesthetics are summarized in Table 26-2. The pharmacokinetics of the ester-based local anesthetics have not been extensively studied owing to their rapid breakdown in plasma (elimination half-life < 1 minute). Local anesthetics are usually administered by injection into dermis and soft tissues around nerves. Thus, absorption and distribution are not as important in controlling the onset of effect as in determining the rate of offset of local analgesia and the likelihood of CNS and cardiac toxicity. Topical application of local anesthetics (eg, transmucosal or transdermal) requires drug diffusion for both onset and offset of anesthetic effect. However, intracavitary (eg, intra-articular, intraperitoneal) administration is associated with a more rapid onset and shorter duration of local anesthetic effect. 

Acute toxicity studies may be conducted by administering the drug by any of several routes (oral, intravenous, intramuscular, intraperitoneal, subcutaneous, or dermal). The route chosen usually is that intended to be used clinically. Rats and mice are generally used for acute toxicity work however, rabbits are commonly used when the route of administration is dermal. 

Vanadium is an element, and as such, is not metabolized. However, in the body, there is an interconversion of two oxidation states of vanadium, the tetravalent form, vanadyl (V+4), and the pentavalent form, vanadate (V+5). Vanadium can reversibly bind to transferrin protein in the blood and then be taken up into erythrocytes. These two factors may affect the biphasic clearance of vanadium that occurs in the blood. Vanadate is considered more toxic than vanadyl, because vanadate is reactive with a number of enzymes and is a potent inhibitor of the Na+K+-ATPase of plasma membranes (Harris et al. 1984 Patterson et al. 1986). There is a slower uptake of vanadyl into erythrocytes compared to the vanadate form. Five minutes after an intravenous administration of radiolabeled vanadate or vandadyl in dogs, 30% of the vanadate dose and 12% of the vanadyl dose is found in erythrocytes (Harris et al. 1984). It is suggested that this difference in uptake is due to the time required for the vanadyl form to be oxidized to vanadate. When V+4 or V+5 is administered intravenously, a balance is reached in which vanadium moves in and out of the cells at a rate that is comparable to the rate of vanadium removal from the blood (Harris et al. 1984). Initially, vanadyl leaves the blood more rapidly than vandate, possibly due to the slower uptake of vanadyl into cells (Harris et al. 1984). Five hours after administration, blood clearance is essentially identical for the two forms. A decrease in glutathione, NADPH, and NADH occurs within an hour after intraperitoneal injection of sodium vanadate in mice (Bruech et al. 1984). It is believed that vanadate requires these cytochrome P-450 components for oxidation to the vanadyl form. A consequence of this action is the diversion of electrons from the monooxygenase system resulting in the inhibition of drug dealkylation (Bruech et al. 1984). 

In contrast to ascorbic acid and a-tocopherol amidothionophosphates did not have any prooxidative effects as measured by oxygen consumption from buffer solutions containing the drug and cupric sulphate as a source of redox-active metal ions (Ti-ROSH et al. 1996). Amidothionophosphates reduced significantly and in a dose-dependent manner the oxygen burst in human neutrophils as measured by luminol-dependent luminescence, and they also markedly depressed the killing of human fibroblasts by mixtures of glucose oxidase and streptolysin S. The toxicity of these molecules was tested by intraperitoneal injection of doses up to 1000 mg/kg to white Sabra mice. No mortality was observed 30 d after administration of up to 500 mg/kg. 

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