scholarly journals Species differences in the metabolism of norephedrine in man, rabbit and rat

1973 ◽  
Vol 136 (3) ◽  
pp. 763-771 ◽  
Author(s):  
Joseph E. Sinsheimer ◽  
L. Graham Dring ◽  
R. Tecwyn Williams
Keyword(s):  
Hippuric Acid ◽  
Species Differences ◽  
Degradation Products ◽  
Human Subjects ◽  
Side Chain ◽  
Unchanged Drug ◽  
Main Metabolite

1. (±)-2-Amino-1-phenyl[1-14C]propan-1-ol ([14C]norephedrine) was administered orally to man, rat and rabbit and the metabolites excreted in the urine were identified and measured. Pronounced species differences in the metabolism of the drug were found. 2. Three male human subjects, receiving 25mg each of [14C]norephedrine hydrochloride, excreted over 90% of the14C in the first day. The main metabolite was the unchanged drug (86% of the dose) and minor metabolites were hippuric acid and 4-hydroxynorephedrine. 3. In rats given 12mg of the drug/kg almost 80% of the14C administered was excreted in the first day. The major metabolites in the urine were the unchanged drug (48% of the dose), 4-hydroxynorephedrine (28%) and trace amounts of side-chain degradation products. 4. Rabbits given 12mg of the drug/kg excreted 85–95% of the dose of14C in the urine in the first 24h after dosing. The major metabolites in the urine were conjugates of 1,2-dihydroxy-1-phenylpropane (31% of the dose) and of 1-hydroxy-1-phenylpropan-2-one (27%) and hippuric acid (20%). The unchanged drug was excreted in relatively small amounts (8%).

scholarly journals Metabolism of [14C]methamphetamine in man, the guinea pig and the rat

1972 ◽  
Vol 129 (1) ◽  
pp. 11-22 ◽  
Author(s):  
J. Caldwell ◽  
L. G. Dring ◽  
R. T. Williams
Keyword(s):  
Guinea Pig ◽  
Benzoic Acid ◽  
Methyl Ketone ◽  
Species Differences ◽  
Human Subjects ◽  
Main Reaction ◽  
Unchanged Drug ◽  
Aromatic Hydroxylation ◽  
Dose Dependent ◽  
Acid Labile

1. The metabolites of (±)-2-methylamino-1-phenyl[1-14C]propane ([14C]methamphetamine) in urine were examined in man, rat and guinea pig. 2. In two male human subjects receiving the drug orally (20mg per person) about 90% of the14C was excreted in the urine in 4 days. The urine of the first day was examined for metabolites, and the main metabolites were the unchanged drug (22% of the dose) and 4-hydroxymethamphetamine (15%). Minor metabolites were hippuric acid, norephedrine, 4-hydroxyamphetamine, 4-hydroxynorephedrine and an acid-labile precursor of benzyl methyl ketone. 3. In the rat some 82% of the dose of14C (45mg/kg) was excreted in the urine and 2–3% in the faeces in 3–4 days. In 2 days the main metabolites in the urine were 4-hydroxymethamphetamine (31% of dose), 4-hydroxynorephedrine (16%) and unchanged drug (11%). Minor metabolites were amphetamine, 4-hydroxyamphetamine and benzoic acid. 4. The guinea pig was injected intraperitoneally with the drug at two doses, 10 and 45mg/kg. In both cases nearly 90% of the14C was excreted, mainly in the urine after the lower dose, but in the urine (69%) and faeces (18%) after the higher dose. The main metabolites in the guinea pig were benzoic acid and its conjugates. Minor metabolites were unchanged drug, amphetamine, norephedrine, an acid-labile precursor of benzyl methyl ketone and an unknown weakly acidic metabolite. The output of norephedrine was dose-dependent, being about 19% on the higher dose and about 1% on the lower dose. 5. Marked species differences in the metabolism of methamphetamine were observed. The main reaction in the rat was aromatic hydroxylation, in the guinea pig demethylation and deamination, whereas in man much of the drug, possibly one-half, was excreted unchanged.

Comparison of the Effect of Imipramine and Desipramine on Some Symptoms of Depressive Illness

1965 ◽  
Vol 111 (478) ◽  
pp. 889-897 ◽  
Author(s):  
Griffith Edwards
Keyword(s):  
Species Differences ◽  
Human Subjects ◽  
Depressive Illness ◽  
Experimental Demonstration ◽  
Laboratory Studies ◽  
Laboratory Findings ◽  
Leptazol Convulsions ◽  
Antidepressant Action

The possibility that desipramine might prove to be a rapidly acting antidepressant was first raised by laboratory studies. In 1959 desipramine was isolated as a metabolite of imipramine (Hermann et al., 1959; Hermann and Pulver, 1960), and a series of papers then followed (Brodie et al., 1961; Gillette et al., 1961; Sulser et al., 1962) in which it was shown that reserpine-induced inactivity in the rat can be more rapidly reversed by desipramine than by imipramine. This was referred to (Gillette et al., 1961) as an experimental demonstration of the relative rapidity of the “antidepressant” action of the two drugs. Other experimental reports should however warn against incautious interpretation of laboratory findings. Garattini et al. (1962) showed that desipramine is not responsible for all the actions of imipramine: in mice, leptazol convulsions are inhibited by the latter but not by the former drug. Dingell et al. (1964) were able to show considerable species differences in the rate at which imipramine is converted to desipramine and in the rate at which desipramine is then destroyed. Their paper also emphasizes the paucity of information on the metabolism of imipramine in human subjects.

scholarly journals The metabolism of14C-labelled α-methyldopa in normal and hypertensive human subjects

1972 ◽  
Vol 129 (1) ◽  
pp. 1-10 ◽  
Author(s):  
W. Y. W. Au ◽  
L. G. Dring ◽  
D. G. Grahame-Smith ◽  
P. Isaac ◽  
R. T. Williams
Keyword(s):  
Human Subjects ◽  
Normal Subjects ◽  
Main Metabolite ◽  
Hypertensive Patients ◽  
The One ◽  
Normal Men

1. The fate of orally administered14C-labelled l-α-methyldopa has been examined in three normal men and in eight hypertensive patients who responded to the drug and three who did not. 2. The output of14C in the urine in 2 days and in the faeces in 4 days was not very different in any of the subjects. The normals excreted about 40% of the dose in the urine and 60% in the faeces, the responders 52% (range 35–60%) and 45% and the non-responders 42% and 41%. Most of the urinary14C radioactivity was eliminated in 24h after dosing. 3. The main metabolite in the urine was free and conjugated α-methyldopa (normal men, 23% responders, 37% non-responders, 25% of the dose). Free and conjugated 3-O-methyl-α-methyldopa was about 4% in all subjects, total amines (α-methyldopamine and 3-O-methyl-α-methyldopamine) about 6% and ketones (mainly 3,4-dihydroxyphenylacetone) about 3%. 4. The output of α-methyldopamine (2–4% of dose), 3-O-methyl-α-methyldopamine (0.3%) and 3,4-dihydroxyphenylacetone (3–5%) was similar in the one normal and two responders examined. 5. The faecal14C in all subjects was unchanged l-α-methyldopa. 6. In general, the amounts of the metabolites in the urine in normal men and in responding and non-responding patients were quantitatively similar, except in one non-responding patient who converted nearly two-thirds of the absorbed drug into amines and ketones. There appeared to be no correlation between metabolites in the urine and response or lack of response to the drug. 7. In two normal subjects 70–80% of d-α-methyldopa was excreted unchanged in the faeces. Of the absorbed compound most (9–14% of the dose) was excreted as the free and conjugated drug together with a small amount (1–2%) of 3-O-methyl-α-methyldopa. No amines and only traces of ketone were excreted.

scholarly journals Substrate Inhibition in the Hydrolysis of Hippuric Acid Esters by Carboxypeptidase A

1975 ◽  
Vol 53 (2) ◽  
pp. 283-294 ◽  
Author(s):  
Joe Murphy ◽  
John W. Bunting
Keyword(s):  
Substrate Concentration ◽  
Hippuric Acid ◽  
Substrate Inhibition ◽  
Competitive Inhibitor ◽  
Side Chain ◽  
Carboxypeptidase A ◽  
Substrate Activation ◽  
Hydrolysis Of ◽  
Substrate Concentrations ◽  
Acid Esters

The dependence of initial velocity upon substrate concentration has been examined in the carboxypeptidase A catalyzed hydrolysis of the following hippuric acid esters (at pH 7.5, 25°, ionic strength O.5): C6H5CONHCH2CO2CHRCO2H: R=CH3; CH2CH3;(CH2)2CH3; (CH2)3CH3; (CH2)5CH3; CH(CH3)2; CH2CH(CH3)2; C6H5; CH2C6H5. All of these esters display marked substrate inhibition of their enzymic hydrolyses. With the exception of R=CH3, the velocity-substrate concentration profiles for each of these esters can be rationalized by the formation of an E.S2 complex which, independent of the alcohol moiety of the ester, reacts approximately 25 times more slowly than the E.S complex. For most of these esters, the formation of E.S2 approximates ordered binding of the substrate molecules at the catalytic and inhibitory sites. While binding at the catalytic site is markedly dependent on the nature of the R group, binding of a second substrate molecule to E.S is not significantly affected by the nature of the R side chain. For R=C6H5, the D ester is neither a substrate nor a competitive inhibitor of the hydrolysis of the L-ester but can replace the L-ester at the binding site which is responsible for substrate inhibition. The kinetic analysis suggests that this behavior of D and L -enantiomers is also typical of the other esters examined (except possibly R=CH3). For R=CH3 only, substrate activation also seems to occur prior to the onset of substrate inhibition at higher substrate concentrations.

scholarly journals The Effect of Enhanced Fibrinolytic Activity on the Red Cell Membrane Transport

1977 ◽  
Author(s):  
S.B. Ulutin ◽  
N. B. Emekli ◽  
T. U. Yardimici
Keyword(s):  
Active Transport ◽  
Fibrinolytic Activity ◽  
Time Course ◽  
Degradation Products ◽  
Human Subjects ◽  
Red Cells ◽  
Fibrinolytic System ◽  
Red Cell ◽  
Red Cell Membrane ◽  
Before And After

In dogs and in human subjects, using hepatic vein catheterization before and after the activation of the fibrinolytic system, the blood samples were obtained and the red cell amino acid transport was investigated. The time course accumulation of radioactive histidine in isolated red cells was followed together with the measurements of the fibrinolytic activity.A decrease in the active transport of histidine was observed in the red cells after the stimulation of the fibrinolytic system. Also a correlation between the decrease of active transport and the increase of fibrin-fibrinogen degradation products was seen.

scholarly journals Characterization of two new degradation products of atorvastatin calcium formed upon treatment with strong acids

2019 ◽  
Vol 15 ◽  
pp. 2085-2091
Author(s):  
Jürgen Krauß ◽  
Monika Klimt ◽  
Markus Luber ◽  
Peter Mayer ◽  
Franz Bracher
Keyword(s):  
Degradation Products ◽  
Crystal Structure Analysis ◽  
Side Chain ◽  
The Novel ◽  
Isopropyl Group ◽  
X Ray ◽  
Atorvastatin Calcium ◽  
Acidic Conditions ◽  
Strong Acids

Atorvastatin calcium (Lipitor®, Sortis®) is a well-established cholesterol synthesis enzyme (CSE) inhibitor commonly used in the therapy of hypercholesterolemia. This drug is known to be sensitive to acid treatment, but only little data has been published on the structures of the degradation products. Here we report the identification of two novel degradation products of atorvastatin, which are formed only under drastic acidic conditions. While treatment with conc. sulfuric acid led to a loss of the carboxanilide residue (accompanied by an expectable lactonization/dehydration process in the side chain), treatment with conc. aqueous hydrochloric acid gave a complex, bridged molecule under C–C-bond formation of the lactone moiety with the pyrrole, migration of the isopropyl group and loss of the carboxanilide residue. The novel degradation products were characterized by NMR spectroscopy, HRMS data and X-ray crystal structure analysis.

METABOLISM OF 6-CHLORO-9α,10α-PREGNA-1,4,6-TRIENE-3,20-DIONE IN RAT, RABBIT, MONKEY AND MAN

1973 ◽  
Vol 74 (1) ◽  
pp. 127-143
Author(s):  
H. Breuer ◽  
D. E. Kime ◽  
R. Knuppen
Keyword(s):  
Human Subjects ◽  
Total Radioactivity ◽  
Female Rats ◽  
Male Rats ◽  
Gas Chromatography Mass Spectrometry ◽  
Main Metabolite ◽  
Polar Metabolite ◽  
Liver Slices ◽  
Authentic Compound ◽  
Female Rhesus Monkey

ABSTRACT When 6-chloro-9β,10α-pregna-1,4,6-triene-3,20-dione (trengestone) was incubated with liver slices of male rats, the substrate was rapidly transformed to a polar metabolite; in contrast, liver slices of female rats metabolised trengestone much more slowly, and only traces of a polar metabolite could be detected. After paper and thin layer chromatography in various systems, the polar metabolite was obtained in crystalline form and identified as 6-chloro-16α-hydroxy-9β,10α-pregna-1,4,6-treiene-3,20-dione (16α-hydroxytreengestone) by its infrared spectrum and by gas chromatography-mass spectrometry. After administration of trengestone to male or female rats, the main metabolite in the urine was again a6α-hydroxytrengestone. When trengestone was incubated with liver slices of male or female human subjects, two metabolites were detected, one of which was formed in large amounts. By comparison with the authentic compound, the major metabolite proved to be identical with (20S)-6-chloro-20-hydroxy-9β,10α-pregna-1,4,6-triene-3-one (20α-hydroxytrengestone). After oral administration of radioactive trengestone to man, the amount of total radioactivity in the urine was considerably greater in a human female (50 %) than in two human males (6–8 %). The main metabolite of trengestone was identified as 20α-hydroxytrengestone. When trengestone was given orally to a female rabbit, and to a female Rhesus monkey, both the 20α-hydroxy and the 2β-hydroxy derivatives of trengestone were detected in the urine. These experiments demonstrate considerable differences in the metabolism of the rat, rabbit, monkey, and man.

scholarly journals Species differences in the metabolism and excretion of sulphasomidine and sulphamethomidine

1969 ◽  
Vol 111 (2) ◽  
pp. 173-179 ◽  
Author(s):  
J W Bridges ◽  
S R Walker ◽  
R T Williams
Keyword(s):  
Partition Coefficients ◽  
Species Differences ◽  
Species Difference ◽  
Acetyl Derivative ◽  
The Other ◽  
Main Metabolite ◽  
Monkey Liver ◽  
Liver Homogenates

1. The excretion of 2,4-dimethyl-6-sulphanilamidopyrimidine (sulphasomidine; Elkosin) and 4-methoxy-2-methyl-6-sulphanilamidopyrimidine (sulphamethomidine) given orally was examined in man, rhesus monkey, rabbit and rat. 2. About 70% of sulphasomidine (0·1g./kg.) is excreted mainly unchanged in the urine by these species in 24hr.; less than 15% of the dose is acetylated and there is no marked species difference in the fate of this drug. 3. Sulphamethomidine is excreted more slowly than sulphasomidine, and in the rat, rabbit and monkey the main metabolite is the N4-acetyl derivative. In man, only 20–30% of the dose is excreted in 24hr. and nearly 70% of this is sulphamethomidine N1-glucuronide, which is also excreted by the monkey but not by the rat or rabbit. There is therefore a marked species difference in the metabolism of sulphamethomidine. 4. Sulphamethomidine N1-glucuronide was synthesized and shown to be identical with the glucuronide isolated from monkey urine. 5. Sulphasomidine, sulphamethomidine and sulphadimethoxine (2,4-dimethoxy-6-sulphanilamidopyrimidine) were acetylated by rabbit or monkey liver homogenates. Although sulphasomidine is poorly acetylated in vivo, it is acetylated in vitro at rates comparable with those of the other two drugs. 6. The solubilities, partition coefficients and plasma-protein-binding of the drugs were measured. 7. The results are discussed.

Incorporation of 13C-Labeled Coniferyl Alcohol into Developing Ginkgo biloba L. Lignin Revealed by Analytical Pyrolysis and CuO Oxidation in Combination with Isotope Ratio Monitoring-Gas Chromatography-Mass Spectrometry

Holzforschung ◽  
2000 ◽  
Vol 54 (1) ◽  
pp. 39-54 ◽  
Author(s):  
T. I. Eglinton ◽  
M. A. Goñi ◽  
J. J. Boon ◽  
E. R. E. van der Hage ◽  
N. Terashima ◽  
...  
Keyword(s):  
Ginkgo Biloba ◽  
Degradation Products ◽  
Chemical Degradation ◽  
Original Position ◽  
Side Chain ◽  
Analytical Pyrolysis ◽  
Isotopic Analyses ◽  
Specific Degradation ◽  
Lignin Macromolecule ◽  
Cuo Oxidation

Summary A suite of four samples of xylem tissue from Ginkgo (Ginkgo biloba L.) shoots grown in a medium containing coniferin 13C-labeled at differing side-chain carbon atoms were studied using thermal and chemical degradation methods in combination with molecular-level isotopic analyses. The aims of the study were threefold: (1) to verify conclusions drawn from Nuclear Magnetic Resonance experiments previously performed on the same tissue samples, (2) to investigate degradation mechanisms and (3) to quantify the proportion of labeled material in each sample. Isotopic analysis of specific degradation products revealed the presence of the label exclusively within lignin-derived (phenolic) products and that the label is retained in its original position on the side-chain. These two results clearly indicate that there is no “scrambling” of carbon atoms as a result of thermal or chemical degradation, and thus lend strong support to analytical pyrolysis and chemolysis as viable approaches for structural investigations of the lignin macromolecule. Indeed, the isotopic enrichment of specific degradation products provides new evidence for certain types of linkages within the lignin polymer. The distribution and isotopic composition of the degradation products also strongly suggest an origin from newly-formed lignin as opposed to DHP-type products or unreacted substrate. As such, the data provides added confidence in the selective labeling approach for elucidation of the structure and biosynthesis of lignin. Isotopic mass balance calculations reveal that certain pyrolysis and CuO oxidation products show enhanced labeling which may be indicative of preferential incorporation of their specific precursors into the growing lignin macromolecule or heterogeneous lignin deposition.

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