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Biomedical subjects

F J Leinweber

Publications and source records attributed to F J Leinweber.

At least 19 recordsLinked to original sources
PubMed1988

Pyrido[2,1-b]quinazolinecarboxamide derivatives as platelet activating factor antagonists.

A series of N-[(heteroaryl)alkyl]pyrido[2,1-b]quinazolines were evaluated for their ability to inhibit the binding of radiolabeled platelet activating factor (PAF) to its receptor on dog platelets. The most potent compounds in this series were found to be pyrido[2,1-b]quinazoline-8-carboxamides possessing a four- or six-carbon chain between the carboxamide nitrogen atom and a 3-pyridinyl or 5-pyrimidinyl moiety. Since earlier metabolism studies with pyridoquinazolinecarboxamides suggest that the carboxamide moiety is labile to hydrolysis in vivo, attempts were made to find isosteric replacements for this group. The substitutions examined led to a loss of activity; however, insertion of a methyl group on the carbon atom alpha to the carboxamide nitrogen led to an enantioselective enhancement of potency. (R)-2-(1-Methylethyl)-N-[1-methyl-4-(3-pyridinyl)butyl]-11-oxo-11H- pyrido[2,1-b]quinazoline-8-carboxamide (34) was more potent than the corresponding S enantiomer in the PAF binding assay and was also shown to be more resistant to degradation by amidases present in whole liver homogenates obtained from guinea pig, dog, and squirrel monkey. The corresponding rac-2-(1-methylethyl)-N-[1-methyl-4-(3-pyridinyl)butyl]-11-oxo-11H- pyrido[2,1-b]quinazoline-8-carboxamide (33) was found to inhibit transient PAF-induced thrombocytopenia and decreases in blood pressure in guinea pigs after intravenous or oral administration and to have a duration of action of greater than 5 h after an oral dose of 200 mg/kg. Compound 33 thus represents the prototype of a new class of orally active PAF antagonists.

Animals↗
PubMed1987

Metabolism of the anti-obesity agent, 4-amino-5-ethyl-3-thiophenecarboxylic acid methyl ester hydrochloride, in rats and dogs.

1. In 24 h, male rats excreted in urine 1% of an intra-gastric 100 mg/kg dose of 4-amino-5-ethyl-3-[4-14C]thiophenecarboxylic acid methyl ester hydrochloride (I) as unchanged I and 59% as 4-amino-5-ethyl-3-thiophenecarboxylic acid (II), mostly conjugated. 2. In rats dosed intra-duodenally with I (50 mg/kg), little I was found in the systemic circulation (less than 2 micrograms/ml) but high concentrations (26 micrograms/ml) were present at five minutes in portal plasma. At five minutes, II was found at 89 and 93 micrograms/ml in systemic and portal plasma, respectively. First-pass ester hydrolysis by the duodenum and liver may explain the near absence of I and the high concentrations of II in systemic plasma. 3. Dogs which received 30 mg/kg 14C-I intra-gastrically, excreted 0.3% I, 30.8% II and 6.8% as 5-ethyl-4-(methylamino)-3-thiophenecarboxylic acid (III), the N-methyl derivative of II. 4. Dogs which received approximately equivalent intra-venous or intra-gastric doses of non-radioactive I and II had high plasma concentrations of II but only small concentrations of I. Plasma concentrations of II after intra-gastric doses of non-radioactive I or II were similar, indicating that both compounds are pharmacokinetically equivalent. I may be a prodrug of II.

Animals↗
PubMed1983

Biotransformation of cibenzoline to 2-(2,2-diphenylcyclopropyl)-1H-imidazole.

A microsomal metabolite of cibenzoline, 4,5-dihydro-2-(2,2-diphenylcyclopropyl)-1H-imidazole butanedioate, was identified by n.m.r. as the 4,5-dehydro analogue, 2-(2,2-diphenylcyclopropyl)-1H-imidazole. Three dogs dosed orally with 13.8 mg/kg 14C-cibenzoline base excreted 1.8-3.5% of the dose as this metabolite in the urine. Mean plasma concentrations of cibenzoline reached a peak of 1.5 micrograms/ml at 2 h while mean concentrations of the metabolite of 0.4-0.5 micrograms/ml were found between 2 and 7 h. The metabolite was synthesized and found to decrease the frequency of ventricular premature depolarizations in conscious dogs having a two-stage occlusion of the left anterior descending coronary artery performed 48 h before. It did not inhibit ventricular arrhythmia in rats induced by i.v. infusion of aconitine. Thus, in contrast to cibenzoline, the metabolite does not appear to be a true antiarrhythmic agent.

Animals↗
PubMed1982

Pharmacodynamic studies with (-)-3-phenoxy-N-methylmorphinan in rats.

Analgesia and brain and plasma concentrations of (-)-3-phenoxy-N-methylmorphinan (PMM) and its metabolites were determined in rats administered 50 mg/kg of 3H-labeled PMM p.o., an approximate ED50. Unchanged PMM and two active metabolites, levorphanol and a different phenol, p-hydroxylated on the 3-phenoxy group (pOH-PMM), were present in brain at concentrations greater than in plasma. Analgesia was observed from 1 to 6 hr and was associated with brain concentrations of 400-1400 ng/g of PMM, 190-300 ng/g of pOH-PMM, and 16-27 ng/g of levorphanol. The presence of 58% of the administered dose as unchanged PMM in the gastrointestinal tract at 6 hr may reflect slow absorption and explain the persisting brain concentrations of PMM and its metabolites as well as the prolonged analgesia. Analgesia may have been due to the presence in brain of only PMM, pOH-PMM or levorphanol, or to the combined activity of two or three of these substances. Administration of the approximate ED50 of 3H-labeled levorphanol (0.1 mg/kg, s.c., or 6 mg/kg, p.o.) resulted in brain levorphanol concentrations (11-18 ng/g) close to those observed when PMM was administered p.o. at 50 mg/kg. After administration of an approximate subcutaneous ED50 of [3H]pOH-PMM of 24 mg/kg, the brains contained pOH-PMM (1500-4100 ng/g) and levorphanol (60-100 ng/g); these levorphanol concentrations were higher than those found after administration of the approximate ED50 of PMM or levorphanol. The findings indicate that brain levorphanol concentrations resulting from administration of PMM or pOH-PMM to rats may account for the analgesic activity observed, i.e. that PMM and pOH-PMM may act as prodrugs for levorphanol

Analgesics↗
PubMed1978

l-Bunolol metabolism in rats: identification of urinary metabolites.

Urine collected for 24 hr from rats given a single oral dose of 3H-l-bunolol (10 mg/kg) was found to contain only 25.8% of the dose and more than 30 labeled compounds. Nine compounds were identified and quantified as follows: bunolol (0.35% of urinary tritium), bunolol glucuronide (5.12%), bunolol sulfate (0.08%), dihydrobunolol (0.08%), dihydrobunolol glucuronide (0.74%), dihydrobunolol sulfate (0.12%), hydroxydihydrobunolol (0.58%), beta-(5-oxytetralonyl)lactic acid (0.74%), and (5-oxytetralonyl) acetic acid glucuronide (1.12%). The total quantity of identified labeled compounds was only 2.3% of the dose and 8.9% of the urinary radioactivity.

Animals↗
PubMed1978

l-bunolol metabolites in human urine.

Nine radiolabeled compounds were identified in human urine after administering a single oral dose of 3H-l-bunolol (3 mg) to 5 male volunteers. These compounds represented 54.7% of the dose and 71.4% of the isotope excreted in 3 days. Intact bunolol accounted for 14.7% of the dose and its conjugates totaled an additional 5.0%. The major drug metabolite (28.2% of dose) was dihydrobunolol, a reduction product known to have the same pharmacological activity and potency as bunolol. Dihydrobunolol conjugates amounted to 3.9% of the dose. Two minor acidic metabolites were produced by oxidative cleavage of the bunolol side chain, and another minor metabolite (hydroxydihydrobunolol) resulted from both reductive and oxidative biotransformation. Bunolol metabolism in man showed qualitative and quantitative differences from patterns observed in the rat and dog.

Acetates↗
PubMed1978

Bunolol metabolism by dogs: urinary excretion of 5-hydroxytetralone.

1. Anion exchange and t.l.c. were used to collect the polar drug metabolites present in urine of dogs treated orally with [14C]bunolol. 2. A new metabolite, 5-hydroxytetralone, was isolated, purified, and identified by u.v.,i.r. and mass spectroscopy. 3. 5-Hydroxytetralone represented 1.7% dose excreted in urine collected for 24 h after bunolol administration. 4. Properties of the metabolite are discussed in relation to the question of whether 5-hydroxytetralone was excreted as a conjugate.

Animals↗
PubMed1977

Metabolism of l-bunolol.

The metabolism of l-bunolol, a new beta-blocking drug, was studied in man after single oral 3-mg doses of 3H-labeled compound. Absorption from the gut was rapid and virtually complete. Peak levels of bunolol and of dihydrobunolol, an active metabolite, were observed at 1 hr. Excretion of the administered radioactivity was mainly into the urine (78% in 4 days), with only 3% appearing in the feces. Bunolol, bunolol glucuronide, bunolol sulfate, dihydrobunolol, and dihydrobunolol glucuronide were identified and quantified in the plasma. These compounds represented 82% of the radioactivity in plasma at 30 min and 55% at 24 hr. Plasma half-lives (+/-S.D.) were estimated to be 6.1 +/- 0.3 hr for bunolol, 9.1 +/- 1.9 hr for bunolol glucuronide, 17.4 +/- 2.5 hr for bunolol sulfate, 7.1 +/- 0.5 hr for dihydrobunolol, and 7.7 +/- 0.8 hr for dihydrobunolol glucuronide.

Adult↗
PubMed1977

Bunolol metabolism by dogs: identification of basic metabolites and their conjugates.

Female beagles dosed once with encapsulated 14C-bunolol (10 mg/kg) excreted 61% of the isotope in urine in 24 hr. The pooled urine contained a minimum of 18 labeled compounds. Two previously unknown metabolites were purified and were identified by UV and mass spectral data; they were hydroxybunolol (10.1% of urinary radioactivity) and hydroxydihydrobunolol (9.8%). The urine also contained bunolol (0.7% of urinary carbon-14), dihydrobunolol (0.5%), conjugated dihydrobunolol (2.8%), beta-(5-oxytetralonyl)lactic acid (16.3%), and (5-oxytetralonyl) acetic acid (7.1%).

Animals↗
PubMed1976

A new oxisuran metabolite.

1. An unidentified oxisuran metabolite which had been observed in animal urine was biosynthesized by incubating [14C]oxisuran with rat liver cytosol. 2. The metabolite, isolated by preparative t.l.c. and extraction, was identified as oxisuran alcohol sulphide by mass fragmentography. Confirmation of this identification was obtained by biosynthesis of the same compound from oxisuran sulphide. 3. The 9000 g supernatant liquid from rat liver was less effective than cytosol in reducing oxisuran to its alcohol sulphide. Neither rat liver fraction reduced oxisuran alcohol sulphoxides to sulphide. 4. The 9000 g fraction oxidized oxisuran and oxisuran alcohol sulphoxide to oxisuran alcohol sulphone.

Animals↗