Biomedical subjects

C W Sigel

Publications and source records attributed to C W Sigel.

41 records · Page 3Linked to original sources

PubMedDate not supplied

The disposition and metabolism of [14C]piritrexim in rats after intravenous and oral administration.

The disposition of [14C]piritrexim in male rats after iv (5 and 10 mg/kg) and po (5, 10, and 20 mg/kg) doses was studied. After an iv dose of 10 mg/kg, rats excreted an average of 57% of the dose in feces and 32% in urine; after a po dose of 10 mg/kg, 84% of the dose was excreted in feces and 9% in urine. After iv doses, the elimination of unchanged drug from plasma was first order, with a t1/2 of 0.6 hr; at any time point, unchanged drug accounted for less than 50% of the total radiocarbon in the plasma. Oral bioavailability of unchanged drug was less than 5%. O-Demethylation and subsequent conjugation were the main pathways of metabolism; the demethyl metabolites of piritrexim were potent inhibitors of dihydrofolate reductase and were cytotoxic to cells in culture. Concentrations of radiocarbon were highest in liver 24 hr after an iv dose, but less than 1% of the radiocarbon was unchanged drug. Concentrations of radiocarbon in liver after po doses were approximately 40% of those attained after equivalent iv doses.

Administration, Oral↗

PubMedDate not supplied

The disposition and metabolism of [14C]piritrexim in dogs after intravenous and oral administration.

The disposition of [14C]piritrexim ([14C]PTX) in male dogs after iv and po doses of 1.8 mg/kg was examined. After either route of administration, greater than 90% of the dose was recovered in the exreta within 72 hr; approximately 20% was recovered in urine and 70% in feces. [14C]PTX was extensively metabolized by dogs; unchanged drug accounted for less than 15% of the dose in the excreta. The O-demethylated metabolites, 2'- and 5'-demethyl PTX, the glucuronide conjugate of 2'-demethyl PTX, and the sulfate conjugate of 5'-demethyl PTX were the major metabolites. Unchanged drug accounted for a large proportion of the drug-related radiocarbon in plasma. The average plasma half-life of PTX after iv administration was 2.6 +/- 0.3 hr, and the average total body clearance was 0.33 +/- 0.13 liter/hr/kg. After po administration, peak plasma concentrations of 0.9 +/- 0.3 micrograms/ml occurred about 1.1 hr after the dose; the absolute oral bioavailability of PTX was 0.63 +/- 0.14. Because the O-demethyl metabolites were active dihydrofolate reductase inhibitors, 2'- and 5'-demethyl PTX were synthesized, and the pharmacokinetics and bioavailability of these compounds in dogs after iv and po administration (5 mg/kg) were examined. The plasma concentration-time data for both compounds after iv doses were described by a two-compartment model, with t1/2 beta = 1.3 and 0.8 hr for the 2'- and 5'- demethyl compounds, respectively. Neither compound showed significant advantages over PTX in terms of pharmacokinetics or bioavailability.

Administration, Oral↗

PubMedDate not supplied

Lipid-soluble inhibitors of dihydrofolate reductase. I. Kinetics, tissue distribution, and extent of metabolism of pyrimethamine, metoprine, and etoprine in the rat, dog, and man.

With the aim of developing anticancer compounds which overcome some of the clinical limitations of the polar dihydrofolate reductase inhibitor, methotrexate, the physicochemical properties, kinetics, and metabolism of a series of lipid-soluble 2,4-diamino-5-phenylpyrimidine folate antagonists have been studied. Metoprine and etoprine, potent inhibitors of mammalian dihydrofolate reductase, were compared with pyrimethamine, a widely used antimalarial drug. The development of assay procedures in our laboratory and the synthesis of radiolabeled compounds have enabled a comparison of the kinetic characteristics and tissue distribution of these compounds in several species. The relative lipophilicities as indicated by the octanol/water partition coefficient are: etoprine (log P = 3.19) greater than metoprine (log P = 2.82) greater than pyrimethamine (log P = 2.69). Etoprine has the greatest affinity for plasma proteins, but all three compounds are bound to human plasma protein by 87% or more at therapeutic concentrations. Pharmacokinetic studies in the mouse, rat, dog, and man indicate that metoprine has the longest plasma half-life in all four species. The mean plasma half-lives in man are: pyrimethamine, 85 hr; metoprine, 216 hr; etoprine, 176 hr.

Adult↗

PubMedDate not supplied

Metabolism and disposition by the rat of 35S-sulfadiazine alone and in the presence of trimethoprim.

The tissue distribution and metabolism of 35S-sulfadiazine (I, SDZ) alone and in the presence of trimethoprim (TMP) was studied in the male rat. In the 72-hr period following a single oral dose (30 mg/kg) of 35S-SDZ/TMP (5/1, w/w), 87% of the radioactivity was recovered in the urine and 15% of the radioactivity was recovered in the feces. The concentrations of drug-related material in the plasma or tissues after 72 hr were less than 0.1 ppm with the exception of the liver (0.13 ppm). Aside from intact drug, the two major urinary metabolites (greater than 5% of the radioactivity in urine) were N4-acetylsulfadiazine (II) and sulfadiazine N4-glucuronide (VI). Three minor urinary metabolites (less than 5%) were identified as N4-acetyl-2-sulfanilamido-4-hydroxypyrimidine (IV), 2-sulfanilamido-4-hydroxypyrimidine (III) and 2-sulfanilamido-5-hydroxypyrimidine (V). Metabolites IV and V are novel metabolites of SDZ and have not been reported previously for any species. The relative amounts of sulfadiazine and its metabolites excreted in the urine and feces as well as the distribution of intact drug and 35S in rat tissues were determined. The metabolites were screened for antibacterial activity; the N4-acetylated metabolites II and IV were inactive, whereas the hydroxypyrimidine metabolites III and V were active against a few organisms but in general much less active than I.

Animals↗

PubMedDate not supplied

Pharmacokinetics and disposition in the rat of a DNA intercalator 502U83.

The pharmacokinetics, metabolism, and qualitative tissue distribution of 502U83, a compound with antineoplastic activity, were examined in the rat. After an oral dose, average maximum plasma concentrations of 5.3 micrograms/ml were achieved at 0.28 hr, indicating rapid absorption of the compound; the bioavailability was estimated to be 62%. After intravenous administration the half-life was 1.73 hr. Autoradiographs of rats dosed intravenously with [14C]502U83 showed the presence of significant levels of radioactivity in the bone marrow, salivary gland, thymus, and lung; highest levels were in the gastrointestinal tract. There was no evidence of penetration of radioactivity into the brain. After an intravenous administration of [14C]502U83, a mean of 94.1% of the dose was recovered in 72 hr, with 46.6% in the urine and 47.5% in the feces. HPLC analysis of the radiocarbon in urine and feces revealed the presence of at least six common radioactive peaks, each representing approximately 2 to 12% of the dose. Biotransformation of 502U83 by the rat mainly involves oxidation of the hydroxyethyl group, and one or both of the hydroxymethyl groups leading to three major metabolites, common to urine and feces. Parent drug was the major component in both urine and feces, respectively, accounting for 18% and 10% of the dose in 48 hr. The glucuronic acid conjugate of the parent drug was a minor metabolite (< 2% of the dose). There was no evidence of metabolism on the anthracene ring.

Animals↗