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PubMed2006

Population pharmacokinetics and bioavailability of motexafin gadolinium (Xcytrin) in CD1 mice following intravenous and intraperitoneal injection.

Motexafin gadolinium (Xcytrin) is an expanded porphyrin macrocyclic compound under development for the treatment of several types of cancer. Currently clinical trials and non-clinical pharmacology and toxicology studies are ongoing. The goals of this open label, four arm, non-crossover bioavailability study were to explore motexafin gadolinium pharmacokinetics, determine the i.p. bioavailability, and define a pharmacokinetic model suitable for descriptive and predictive use. Mice received one or seven daily i.v. or i.p. injections (40 mg/kg) then blood samples were collected and analyzed. Plasma concentration data were modelled using population pharmacokinetic methods and a two compartment model was the most appropriate model. The stability and predictive performance of the model were evaluated using bootstrap procedures. The accuracy of the predicted concentrations was 8.3%. Motexafin gadolinium was rapidly cleared from the plasma and although T(1/2beta) was 12.9 h there was no accumulation following seven doses. The i.p. bioavailability was 87.4% and higher plasma concentrations were sustainable for a longer period with i.p. dosing. V(c) was larger than the blood volume and the tissue compartment volume was 38% of V(c), suggesting motexafin gadolinium was not widely distributed into less well perfused tissues. The pharmacokinetic profile in this study was similar to that in oncology patients administered multiple doses of motexafin gadolinium. The unbiased model yields reliable parameter estimates and insight into the pharmacokinetics of motexafin gadolinium in mice, is suitable for both descriptive and predictive purposes, and is a valuable tool in the planning, analysis, and interpretation of pharmacology and toxicology studies in mice.

Animals↗
PubMed1993

Neurotoxicity of glycidamide, an acrylamide metabolite, following intraperitoneal injections in rats.

Acrylamide (2-propenamide) monomer produces central-peripheral distal axonopathy in humans and some animal species. Its neurotoxicity is characterized by abnormal sensation, decreased motor strength, and ataxia. Acrylamide forms adducts with glutathione, proteins, and DNA. Recent studies demonstrated that acrylamide is metabolized to its epoxide, glycidamide (2,3-epoxy-1-propanamide). We studied the neurotoxicity potential of glycidamide in male Sprague-Dawley rats. Animals (groups of 6) were injected ip daily with either aqueous acrylamide or glycidamide at an acrylamide-equivalent dose of 50 mg/kg (0.70 mmol/kg). Both treatments resulted initially in the rats circling, which was followed by the onset of ataxia at 7-9 d and hindlimb paralysis at 12-14 d. Treated animals showed muscle wasting. At termination, acrylamide- and glycidamide-treated rats weighed 105% and 86% of initial weight, respectively, compared to 145% for controls. Animals were anesthetized and perfused with 10% neutral phosphate-buffered formalin 12 or 14 d after beginning of treatment. Both treatment groups exhibited similar neuropathologic changes in the central and peripheral nervous systems. More severe lesions were produced by glycidamide. A marked increase in the number of affected Purkinje cells in the cerebellum, which exhibited changes ranging from pyknosis to cell death, were present. The brainstem exhibited axonal degeneration with chromatolytic necrosis in midbrain medial and lateral reticular nuclei. The spinal cord was characterized by spongy form changes with vacuoles of different sizes in various levels. These results suggest that glycidamide is an active neurotoxic metabolite of acrylamide.

Acrylamide↗
PubMed1979

Acrylic microspheres in vivo. I. Distribution and elimination of polyacrylamide microparticles after intravenous and intraperitoneal injection in mouse and rat.

Microspheres of 14C-labeled highly cross-linked polyacrylamide (mean diameter 0.25-0.30 micron) have been prepared by emulsion polymerization. The label was introduced in the polymer via the cross-linking monomer. N,N'-[14C]methylenebisacrylamide. The microparticles were used to follow qualitatively and quantitatively the distribution and the fate of polyacrylamide in mouse and rat after i.v. and i.p. injection. The polyacrylamide particles are rapidly cleared from the circulation (t 1/2 in rat approximately 40 min) by macrophages of the reticuloendothelial system. They are mainly (about 80%) found in the liver and spleen both after i.v. and i.p. injection (4.1 mg given totally to mice weighing 20-25 g). They can also be detected early (1 hr after i.v. injection) in the bone marrow, and particle aggregates are also initially found in the lungs, although no respiratory problems were noted. After about 16 weeks, the radioactivity rapidly decreases in the liver and spleen, with t 1/2 10 to 14 weeks and 15 to 24 weeks, respectively, depending on the route of administration. Radioactivity in the gut and gut walls detected 2 months after injection suggests that the polyacrylamide is slowly metabolized. No toxic effects-apart from transient hepatospleenomegaly-were detected in mice 45 weeks after they were given a total of 9.8 mg of polyacrylamide.

Acrylamides↗