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M Chadwick

Publications and source records attributed to M Chadwick.

27 records · Page 2Linked to original sources
PubMedDate not supplied

Comparative metabolism and disposition of furfural and furfuryl alcohol in rats.

The comparative metabolism and disposition of furfural (FAL) and furfuryl alcohol (FOL) were investigated following oral administration of approximately 0.001, 0.01, and 0.1 of the LD50, corresponding to approximately 0.127, 1.15, and 12.5 mg/kg for FAL and 0.275, 2.75, and 27.5 mg/kg for FOL. At all doses studied, at least 86-89% of the dose of FAL or FOL was absorbed from the gastrointestinal tract. FAL and FOL were extensively metabolized prior to excretion. The major route of excretion was in urine, where 83-88% of the dose was excreted, whereas 2-4% was excreted in the feces. Approximately 7% of the dose from rats treated with FAL at 12.5 mg/kg was exhaled as 14CO2. At 72 hr following administration, the pattern of tissue distribution of radioactivity was similar for both FAL and FOL. Liver and kidney contained the highest, and brain the lowest concentrations of radioactivity. Generally, the concentrations of radioactivity in tissues were proportional to the dose. Almost all of the urinary radioactivity was tentatively identified. No FAL or FOL was detected in urine. Furoylglycine was the major urinary metabolite (73-80% of dose), and furoic acid (1-6%) and furanacrylic acid (3-8%) were the minor metabolites following treatment with either FAL or FOL. Therefore, the initial step in the metabolism of FAL and FOL involves the oxidation to furoic acid, which is excreted unchanged and decarboxylated to form 14CO2, conjugated with glycine, or condensed with acetic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Effect of dose on the percutaneous absorption of 2- and 4-chloronitrobenzene in rats.

The effect of dose on the dermal absorption of 2- and 4-chloronitrobenzene (2- and 4-CNB) has been investigated in rats following nonocclusive protective dermal application on an area of 4 cm2 per animal at approximately 0.0325, 0.325, and 3.25 mg/cm2 (0.65, 6.5, and 65 mg/kg, respectively). At the three-dose levels, 33-40% and 51-62% of the dose of 2- and 4-CNB, respectively, was absorbed from the skin within 72 hr. The balance of the dose was recovered in the protective device and the organic trap (i.e. that portion unavailable for dermal absorption). The absorbed radioactivity was excreted in urine (21-28% of dose, 2-CNB; 43-45%, 4-CNB) and feces (11-15%, 2-CNB; 5-12%, 4-CNB). The extent and rate of dermal absorption and urinary and fecal excretion of 2-CNB were linear over the 0.65-65 mg/kg dose range; for 4-CNB they were linear over the 0.65-6.5 mg/kg dose, and nonlinear at the 65 mg/kg dose.

Administration, Cutaneous↗
PubMedDate not supplied

Comparative physiological disposition of ellipticine in several animal species after intravenous administration.

The physiological dispositon of ellipticine (NSC 71795) has been studied in the mouse, rat, dog and monkey after administration of [1-14C]ellipticine at 6 mg/kg iv (3 mg/kg to monkey). Ellipticine was very rapidly distributed from the blood of all species and was deposited in tissues. The rate of elimination of ellipticine from blood was species-dependent, half-times ranging from 22 min in mouse to 210 min in rat, and probably reflected the rate of metabolism of the drug. The rate of elimination of metabolites from blood was also species-dependent, half-times ranging from 140 min in mouse to 380 min in rat, and probably reflected the rate of biliary secretion of the metabolites. Ellipticine was widely but not uniformly distributed throughout the tissues including brain, and some of the highest concentrations of drug and metabolites were in liver, which is probably the primary site of metabolism. The concentrations of ellipticine and metabolites in tissues were species-dependent, correlating with species differences in rates of metabolism and excretion. All species excreted 80% of the dose via the fecal route and 10% via the urinary route, primarily as metabolites during the first 24 hr after dosing. Metabolites entered the gastrointestinal tract by biliary secretion and ellipticine entered by an ion-trapping mechanism. Evidence is presented that the major pathway for ellipticine metabolism in rat was to 9-hydroxyellipticine, which did not accumulate in liver but was conjugated to its glucuronide and sulfate, which were secreted in bile. Other pathways involved hydroxylation and glucuronide conjugation. The pharmacokinetics of ellipticine are correlated with its toxic side effects, such as acute hypotention and neurological symptoms. They are also correlated with its potential as an antitumor agent, such as its ability to achieve values for the area under the curve of concentration vs. time (CXt) in tumors, which would be adequate for therapy. Based upon these correlations, the drug should be administered in the clinic by iv infusion, or, provided its bioavailability is found to be satisfactory, by the oral route.

Alkaloids↗
PubMedDate not supplied

Characterization of the metabolites of ellipticine in rat bile.

The two major metabolites of ellipticine (NSC 71795) were isolated from rat bile by a combination of solvent extraction, partition column chromatography, and reverse phase high-performance liquid chromatography. Purification and structural elucidation of the bile products were aided by administration of the drug with a dual label (14C and 2H). The two metabolites were shown to be the sulfate and glucuronide conjugates of 9-hydroxyellipticine by chemical, enzymatic, and mass-spectral fragmentation comparison with synthetic and enzymatically prepared reference compounds.

Alkaloids↗
PubMedDate not supplied

Disposition of the flame retardant 1,2-bis(2,4,6-tribromophenoxy)ethane in rats following administration in the diet.

[14C]1,2-Bis(2,4,6-tribromophenoxy)ethane (FF-680) was administered at 0.05, 0.5, or 5% in the diet for 1 day to three groups (four rats per group) of rats, and daily at 0.05% in the diet for 10 days to another group of five rats. In addition, another group of four rats were given a single oral gavage dose of 200 mg/kg of [14C]FF-680 in corn oil and were used for bile collection. At all dose levels, [14C]FF-680-derived radioactivity was excreted almost totally via the fecal route (> 99% of the total excreted 14C), with < 1% recovered in the urine. No radioactivity was detected in the expired air, and very little radioactivity was excreted in the bile (ca. 0.04% of the dose). At 4 days after the start of administration of the dosed diet for 1 day, no radioactivity was detected in any tissue analyzed, except adipose tissue, skin, and thymus, in which trace concentrations of radioactivity were detected in some animals. At 10 days after the start of administration of dosed diet to rats dosed for 10 days, trace but detectable levels of radioactivity were observed in all tissues analyzed except the brain of some animals. Excluding the gastrointestinal tract, adipose tissue contained the highest concentration of 14C radioactivity, followed by kidney, skin, and thymus, whereas brain, testes, and spleen contained the lowest concentrations of radioactivity. No parent compound was detected in the urine, while fecal radioactivity was identified as the parent compound. Mean recovery of radioactivity ranged from ca. 86-101% of the [14C]FF-680 consumed. The data indicate that FF-680 was very poorly absorbed from the gastrointestinal tract. However, following daily administration for 10 days, trace amounts of radioactivity accumulated in tissues to provide detectable levels.

Animals↗