Showing papers on "Metabolite published in 1980"
TL;DR: It is found that Phenacetin absorption depends on formulation, and it is extensively metabolized to paracetamol and minor metabolites are probably responsible for toxicity.
Abstract: 1 The rate of absorption of oral paracetamol depends on the rate of gastric emptying and is usually rapid and complete. The mean systemic availability is about 75%. 2 Paracetamol is extensively metabolized and the plasma half-life is 1.5-2.5 hours. About 55% and 30% of a therapeutic dose is excreted in the urine as glucuronide and sulphate conjugates, respectively, whereas mercapturic acid and cysteine conjugates (representing conversion to a potentially toxic intermediate metabolite) each account for some 4% of the dose. Paracetamol metabolism is age- and dose-dependent. 3 With hepatotoxic doses, paracetamol metabolism is impaired and the half-life prolonged. Sulphate conjugation is saturated and the proportion excreted as mercapturic acid and cysteine conjugates is increased. 4 The renal clearance of paracetamol depends on urine flow rate by not pH. The renal clearances of the glucuronide and sulphate conjugates often exceed the glomerular filtration rate and are independent of urine flow and pH. 5 Phenacetin absorption depends on formulation. It is extensively metabolized to paracetamol and minor metabolites are probably responsible for toxicity.
419 citations
TL;DR: In young infants under 2 months of age valproic acid elimination half-life can be 60 hours, but in older children, plasma elimination appears to be identical to the adult situation, and the lower value of the therapeutic plasma concentration range of valProic acid is around 50μg/ml.
Abstract: Valproic acid is rapidly absorbed from the gastrointestinal tract, peak concentrations being attained 1 to 2 hours after administration of the conventional tablet, but later with the enteric-coated tablets. The bioavailability of valproic acid is complete and independent of the preparation used. The apparent volume of distribution is relatively small (0.1 to 0.4 L/kg), due to high plasma protein binding. Protein binding is decreased in patients with renal insufficiency, in patients with chronic liver disease, and possibly in the presence of other displacing agents. The total plasma clearance of valproic acid is in the range of 5 to 10ml/min. Plasma elimination half-life is between 10 and 16 hours, and does not change after continued treatment with valproic acid alone. In combination therapy with other antiepileptic drugs, the half- life can be as short as 6 to 8 hours due to liver enzyme induction. Renal excretion of unchanged valproic acid accounts for only 1 to 3% of the total dose. Valproic acid is present in cerebrospinal fluid in concentrations equal to the unbound drug in plasma (around 10% of the total concentration). Valproic acid concentration in saliva is less than and unrelated to the free drug concentration in plasma. The drug is excreted into breast milk and evidence suggests that it also crosses the placenta. Four independent metabolic pathways — glucuronidation, β-oxidation and ω-oxidation (ω1, and ω2) have been demonstrated in man. Analytical difficulties caused by the similarity of the metabolites with many normal endogenous compounds and by chemical lability of several metabolites impede the isolation, identification and especially the quantification of valproic acid metabolites. Quantitative aspects of metabolism are essential for the understanding of drug effects in patients. The main metabolite 3-oxo-valproic acid shows comparable pharmacological activity to valproic acid itself in mice; unsaturated metabolites also show some activity. In young infants under 2 months of age valproic acid elimination half-life can be 60 hours, but in older children, plasma elimination appears to be identical to the adult situation. Valproic acid elimination is impaired in acute viral hepatitis and in liver cirrhosis. No information is available on valproic acid kinetics in renal insufficiency. Phenobarbitone plasma concentrations rise under combination therapy with valproic acid, because phenobarbitone elimination is impaired. Valproic acid lowers total plasma concentrations of phenytoin by displacing it from its plasma albumin binding site, but free phenytoin concentrations remain unchanged and phenytoin doses need not be modified. Valproic acid elimination is enhanced in the presence of inducing drugs like phenobarbitone, primidone, phenytoin and carbamazepine. The valproic acid dose-plasma concentration relationship is curvilinear, since valproic acid protein binding decreases with higher concentrations. Therefore, the increase in the plasma concentration is smaller than expected from the dose increase. The lower value of the therapeutic plasma concentration range of valproic acid is around 50μg/ml. Because of low clinical toxicity the upper value of the therapeutic range has yet to be determined.
341 citations
TL;DR: The amelioration of obsessive-compulsive symptoms was positively correlated to the reduction of CSF concentrations of 5-HIAA during clomipramine treatment but negatively correlated to plasma concentrations of clomIPramine.
Abstract: Concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the dopamine metabolite homovanillic acid, and the noradrenaline metabolite 4-hydroxy-3-methoxyphenyl glycol were measured in CSF before and after three weeks' treatment of severe obsessive-compulsive disorder with clomipramine hydrochloride. Patients who responded to clomipramine treatment had significantly higher CSF levels of 5-HIAA before treatment. The amelioration of obsessive-compulsive symptoms was positively correlated to the reduction of CSF concentrations of 5-HIAA during clomipramine treatment but negatively correlated to plasma concentrations of clomipramine. Reduction of CSF concentrations of 5-HIAA, which probably reflects drug action on central serotonin neurons, was maximal at a plasma clomipramine concentration of about 300 nmole/L. At higher levels, the reduction of CSF levels of 5-HIAA was smaller. The antiobsessive effect of clomipramine may be connected to its capacity to inhibit serotonin uptake.
298 citations
TL;DR: It is argued that activation and inhibition of histamine secretion, phosphatidylinositol labelling and metabolite leakage are all initiated by ATP4- acting at the same receptor.
Abstract: The concentration-dependence on exogenous ATP of activation and inhibition of mast-cell histamine secretion, phosphatidylinositol labelling and leakage of metabolites shows that all these functions are regulated by the free acid ATP4-. Maximal histamine secretion and phosphatidylinositol labelling occur with ATP4- at approx. 2 microM, but higher concentrations, which cause inhibition of secretion and phosphatidylinositol labelling, are required to maximize leakage of 32P-labelled metabolites. Both enhancement and inhibition of phosphatidylinositol labelling (due to low and high concentrations of ATP4- respectively) are rapid in onset; histamine secretion is characterized by a delay, especially at low concentrations of ATP4- (approx. 1 microM). Phosphatidylinositol labelling and histamine secretion are dependent on extracellular Ca2+. Metabolite leakage due to the presence of exogenous ATP4- is slow and does not require Ca2+. Of 18 analogues of ATP that were tested, only four were agonists for secretion, and only these four permitted leakage of 32P-labelled metabolites. It is argued that activation and inhibition of histamine secretion, phosphatidylinositol labelling and metabolite leakage are all initiated by ATP4- acting at the same receptor. For mast cells stimulated with ATP4- enhancement of phosphatidylinositol metabolism is not sufficient by itself to cause Ca2+-dependent secretion.
231 citations
TL;DR: Results indicate that the release of dopamine from particular groups of central neurons is increased during feeding and suggest that anatomically distinct subgroups of central dopaminergic neurons serve different roles in the regulation of food intake.
Abstract: Feeding induced by food deprivation is accompanied by an increased production of the dopamine metabolite 3,4-dihydroxyphenylacetic acid in the brains of rats This neurochemical change occurs in the nucleus accumbens, the posterior hypothalamus, and the amygdala but not in other dopaminergic nerve terminal fields such as the corpus striatum These results indicate that the release of dopamine from particular groups of central neurons is increased during feeding and suggest that anatomically distinct subgroups of central dopaminergic neurons serve different roles in the regulation of food intake
217 citations
TL;DR: Mouse peritoneal macrophages that had ingested zymosan particles released a polar metabolite of arachidonic acid possessing slow-reacting substance activity in the guinea pig ileum assay, consistent with the structure of leukotriene C, an adduct of arACHidonic Acid and glutaathione.
Abstract: Mouse peritoneal macrophages that had ingested zymosan particles released a polar metabolite of arachidonic acid possessing slow-reacting substance activity in the guinea pig ileum assay. The metabolite was purified by solvent extraction, Sephadex G-25 column chromatography. The purified metabolite absorbed light at 280 nm and contained a free amino group. When macrophages were preincubated overnight with [3H]arachidonic acid, [35H]cysteine, or [14C]glutamic acid, each radiolabel was incorporated into the compound. Direct amino acid analysis revealed glycine, glutamic acid, and cysteine at molar ratios of 0.97:1.00:0.82. The above data were consistent with the structure of leukotriene C, an adduct of arachidonic acid and glutaathione. Quantification of the leukotriene C based on incorporation of [3H]arachidonic acid or amino acid analysis indicated that 6 X 10(7) macrophages (3.6 mg of cell protein) released 7.5 nmol after a maximal phagocytic stimulus. The purified leukotriene C had a slow reacting substance activity of 11,500 units/nmol (1 unit has the activity of 5 ng of histamine in a guinea pig ileum contraction assay).
185 citations
TL;DR: A complete perspective on the role of the kidney in pharmacologic and toxicologic processes is dependent on a thorough understanding of the drug and chemical metabolic capabilities of this organ.
181 citations
TL;DR: It is concluded that the causes of the induction lag in protoplasts can differ from those in isolated chloroplasts, and it is suggested that fructose-1,6-bisphosphatase and ribulose- 1,5-bisPhosphate carboxylase may limit flux in the Calvin cycle during induction.
172 citations
TL;DR: CSF metabolite and CSF probenecid concentrations were significantly correlated in depressed patients for all metabolites, and there was decreased postprobenecid accumulation of homovanillic acid in the CSF of depressed patients compared with schizophrenic patients and with normal subjects.
Abstract: The authors report cerebrospinal fluid (CSF) concentrations of five monoamine metabolites before and after probenecid administration in normal subjects and patients with depression and schizophrenia. No differences were found in baseline metabolite concentrations among the three groups. CSF metabolite and CSF probenecid concentrations were significantly correlated in depressed patients for all metabolites, and there was decreased postprobenecid accumulation of homovanillic acid in the CSF of depressed patients compared with schizophrenic patients and with normal subjects. The authors propose a method for correcting for probenecid concentrations. Data from normal subjects should be of value for other investigators using the probenecid technique.
157 citations
TL;DR: The Nitrogen Atom in the Antibiotic Molecule and the Regulation of Catabolic Reactions by Ammonia in Fungi are studied.
Abstract: INTRODUCTION ...... . . . . . . . . . . . . . . .... . . . . . . . ......... . . . . . . ........ 210 RELATIONSHIP BETWEEN GROWTH AND ANTIBIOTIC PRODUCTION 2 1 1 NITROGEN METABOLISM AND ANTIBIOTIC BIOSYNTHESIS ..... . . . . . . . . ....... 212 Nitrogen Nutrition and Antibiotic Production 212 The Origin oj the Nitrogen Atom in the Antibiotic Molecule ........ ... .. .. ... ... .. 213 Direct precursors ... 21 J Nitrogen transfer reactions ... ....... . . . . . . . . . . . . . . . .... . . . ........ . . . . . . . . . . . . . . . . . . . . . . 214 Regulatory Functions Exerted by Primary Nitrogen Metabolites 216 GENERAL NITROGEN METABOLITE REGULATION ... . . . . . . . ... . . . . . . . . . . . . ... 217 Microbial Nitrogen Assimilatory Mechanisms 217 The Involvement oj Glutamine Synthetase in Regulation of Degradative Pathways 218 Metabolic Regulation oj Catabolic Reactions by Ammonia in Fungi ...... 219 NITROGEN METABOLITE REGULATION IN ANTIBIOTIC PRODUCTION . . . . . . . . . . . . .. . . . . . . . . . . . .. .. . . . . . . . . . . . . .. . . . . . . . . 220 Antibiotic Biosynthesis in Streptomycetes 220 fJ-Lactam antibiotics ... .. 220 Nourseothricin .......•... 221 Erythromycin ..... ........ . . . . . . . ....... . . . . . . . . . ......... 222 f3-Lactam Antibiotic Biosynthesis in Fungi 222 Cephalosporin C .•• •. 222 Penicillin ... ......... ......... 223 TRANSPORT CAPACITY AND AMINO ACID POOL COMPOSITION 224 Ammonium Transport 224 Ammonium Effect on Amino Acid Transport in Fungi 225 Control oj Amino Acid Transport in Bacteria 225 Intracellular Concentrations of Free Amino Acids During the Growth Cycle ........ 226
139 citations
TL;DR: Oscillatoria sp., strain JCM grown photoautotrophically in the presence of naphthalene oxidized the aromatic hydrocarbon to cis-1, 2-dihydroxy-1-2-dhydronaphthalenes, 4-hydroxy- 1-tetralone and 1-naphthol.
Abstract: SUMMARY: Oscillatoria sp., strain JCM grown photoautotrophically in the presence of naphthalene oxidized the aromatic hydrocarbon to cis-1,2-dihydroxy-1,2-dihydronaphthalene, 4-hydroxy-1-tetralone and 1-naphthol. The major metabolite was 1-naphthol. Each product was isolated and shown to have ultraviolet and mass spectra identical to those of authentic compounds. In addition, each metabolite had properties identical to those of authentic compounds when analysed by thin-layer, high-pressure liquid and gas-liquid chromatography. Experiments with [14C]naphthalene showed that, over a 24 h period, the organism oxidized 4.8 % of the added naphthalene. The ratio of organic-soluble to water-soluble metabolites was 41:59. Incubation of whole organisms with naphthalene and 18O2 led to the isolation of 1-naphthol that contained 18O. The organism oxidized 1-[14C]naphthol to 4-hydroxy-1-tetralone. The mechanism of naphthalene oxidation by this cyanobacterium is discussed.
TL;DR: The hypothetical combination of an EPA-rich diet and a thromboxane synthetase inhibitor might abolish production of the pro-aggregatory species, throm boxane A2, and enhance formation of the anti-aggRegatory metabolite, prostacyclin.
TL;DR: In this article, labeled and unlabeled prostacyclin and 6-keto-PGF1 alpha were infused into healthy volunteers; urine was chromatographed on different systems including high pressure liquid chromatography.
TL;DR: Patients had various specific disorders of the nervous system, though patients with movement disorders and biochemical defects known to affect the neurotransmitter systems examined in this study were specifically avoided.
Abstract: Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) were measured in lumbar cerebrospinal fluid from a group of patients ranging in age from 1 week to 45 years. Quantitation of these biogenic amine metabolites was achieved using a gas chromatographic/mass spectrometric technique. The subjects had various specific disorders of the nervous system, though patients with movement disorders and biochemical defects known to affect the neurotransmitter systems examined in this study were specifically avoided.
The results indicated a strong inverse correlation in children between CSF HVA and 5-HIAA concentrations and age. The decline in these metabolites with age appeared to be exponential. No significant age effect was observed for MHPG. The results indicate the importance of comparing CSF metabolite levels in children with values in age-matched controls.
Journal Article•
TL;DR: The major metabolites of prostacyclin and 6-keto-prostaglandin F1 alpha in man were investigated and it was concluded that the major metabolite of PGI2
Abstract: The major metabolites of prostacyclin and 6-keto-prostaglandin F1 alpha in man were investigated. Healthy male volunteers were infused with the labeled and unlabeled prostanoids. The urine was chromatographed on different systems including high-pressure liquid chromatography (HPLC). The material under the major peak was derivatized to the methyl ester methoxime trimethyl silyl ether and analyzed by gas chromatography-mass spectrometry (GC-MS). Open bed reversed-phase chromatography of the urine obtained from PGI2 infusion resulted in two peaks. On further separation by two different HPLC systems one major peak containing 20.5 % of the radioactivity was obtained and was shown by GC-MS to be identical with dinor-6-keto-prostaglandin F1 alpha. Urine obtained from 6-keto-prostaglandin F1 alpha infusion was chromatographed similarly. Its major peak on HPLC appeared with a retention volume and mass spectrum identical with the major metabolite of PGI2. It is concluded that the major metabolite of PGI2 and 6-keto-prostaglandin F1 alpha in human urine is dinor-6-keto-prostaglandin F1 alpha.
TL;DR: The results indicate that rat liver microsomes activate benzene via phenol and hydroquinone to p -benzosemiquinone and/or p-benzoquinone as quantitatively important reactive metabolites.
TL;DR: The metabolism of 14C-labeled chenodeoxycholic, cholic, and dexycholic acids was studied in patients with intrahepatic cholestasis and radioactivity appeared to be associated with trihydroxycholanoates.
TL;DR: It is concluded that the binding characteristics in vitro of ligands on the cytosol R do not presently allow us to discriminate between agonist and antagonist ligands.
TL;DR: The results indicate 1) when TxB 2 is measured in plasma, the use of prostaglandin synthesis inhibitor in the collection tubes is necessary and 2) the measurement of TXB 2 in serum of blood which has been kept at +37°C for a strictly standardized period of time could replace the useof PRP in Tx B 2 studies.
Journal Article•
TL;DR: The antineoplastic activity of 5'-dFUrd may be dependent on its enzymatic conversion of FUra, and the basis for the possible increase in therapeutic index compared with other fluoropyrimidines may involve the rate and duration of the production of the biologically active nucleotides 5-fluorouridine 5'-triphosphate and FdUMP.
Abstract: 5′-Deoxy-5-fluorouridine (5′-dFUrd; Roche 21-9738) is a recently synthesized antineoplastic agent with therapeutic potential. The sensitivity of Ehrlich ascites tumor cells in CF-1 mice to 5′-dFUrd, as well as to 5-fluorouracil (FUra), 5-fluoro-2′-deoxyuridine, and 5-fluorouridine, was established. 5′-dFUrd was a more effective antitumor agent and was less toxic over a wide dosage range (50 to 400 mg/kg) than the other agents tested as measured by: ( a ) the ability to prevent gross development of inoculated tumor; ( b ) 45-day survival; and ( c ) weight change over the treatment period. With use of these sensitive tumor cells, the intracellular metabolism of 5′-dFUrd in vitro was investigated. Utilizing liquid chromatographic methodology for separation of acid-soluble metabolites, the only detectable metabolic products of 5′-dFUrd were FUra, 5-fluorouridine 5′-monophosphate, and 5-fluorouridine 5′-triphosphate. Novel metabolites of 5′-dFUrd were not detectable in the acid-soluble fraction or in plasma isolated from mice given [ 14 C]5′-dFUrd. The formation of FUra appears to result from the action of nucleoside phosphorylase. 5′-dFUrd was shown to have a K m of 0.633 mm for this enzyme isolated from Ehrlich ascites tumor cells, an affinity similar to that for 5-fluoro-2′-deoxyuridine (K m , 0.278 mm) but much lower than that for 5-fluorouridine (K m , 0.049 mm). Incorporation of radiolabeled drug into the acid-insoluble fraction (representing greater than 95% incorporation into RNA) was also significant. 5-Fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP) was not detectable as an acid-soluble metabolite. However, significant inhibition of thymidylate synthetase activity was detectable by 20 min in cells incubated with 30 µm 5′-dFUrd, suggesting that FdUMP was produced. The production of both 5-fluorouridine 5′-triphosphate and FdUMP appears dependent on the initial expansion of the FUra pool. This correlates with the inability of 5′-dFUrd to form nucleotide directly due to the absence of a 5′-hydroxyl group. It is concluded that the antineoplastic activity of 5′-dFUrd may be dependent on its enzymatic conversion to FUra. The basis for the possible increase in therapeutic index compared with other fluoropyrimidines may involve the rate and duration of the production of the biologically active nucleotides 5-fluorouridine 5′-triphosphate and FdUMP.
TL;DR: The presence of dinor and pentanor derivatives of 6-keto-PGF1α indicated that β -oxidation and oxidative-decarboxylation occurs in the liver as the major metabolic pathway of PGI2.
TL;DR: It was found that nifedipine was absorbed, metabolized, and excreted rapidly, and that the main metabolite was M-I, which is a new major metabolite found in both dog and human urine.
Abstract: The urinary metabolites of nifedipine in a dog were isolated and identified by chromatographic and spectrometric techniques. A new major metabolite, 2, 6-dimethyl-4-(2-nitrophenyl)-5-methoxycarbonylpyridine-3-carboxylic acid (M-I), was found in both dog and human urine. A highly sensitive and specific method is described for the determination of nifedipine, M-I, and a previously reported metabolite. The method for analysis of nifedipine is based on the oxidation of nifedipine to its pyridine analog, benzene extraction, and determination by electron-capture gas chromatography. The method for analysis of the metabolites is based on ethyl acetate extraction of the acidified specimen, derivatization of M-I to its methyl ester, and determination by electron-capture gas chromatography. Quantitative determination was possible down to 5 ng/ml of nifedipine using 1 ml samples of biological specimens. This method was used to measure plasma levels of nifedipine and its metabolites in dogs, and urinary excretion by humans after oral administration of a nifedipine preparation. It was found that nifedipine was absorbed, metabolized, and excreted rapidly, and that the main metabolite was M-I.
Journal Article•
TL;DR: The data indicate that estradiol-17 beta-D-glucuronide is toxicologically active and suggest the possibility that this estrogen metabolite may induce hepatic pathology in vivo.
Abstract: Estradiol-17 beta-D-glucuronide induced an immediate, profound and reversible inhibition of bile flow after its i.v. administration in the rat. The degree of cholestasis was dose-dependent in the range of 8.5 to 21 mumol/kg i.v. A dose of 11 mumol/kg i.v. inhibited bile flow and bile acid secretory rate 65 to 70% within 15 to 30 min of its administration; bile flow and bile acid secretion had returned to near control values within 3 hr. Linear regression analysis of the relationship between bile flow and bile acid secretion indicated a substantial decrease in bile acid independent flow. In contrast, neither estradiol-17 beta, estradiol-3-glucuronide nor estradiol-3-sulfate-17 beta-D-glucuronide at an equimolar dose had any inhibitory effect on these parameters. After a dose of [3H]estradiol-17 beta-D-glucuronide, 79% of the administered radioactivity was excreted in the bile in 3 hr. Estradiol-3-sulfate-17 beta-D-glucuronide was tentatively identified as the predominant biliary metabolite with estradiol-17 beta-D-glucuronide also present in substantial amounts. These data indicate that estradiol-17 beta-D-glucuronide is toxicologically active and suggest the possibility that this estrogen metabolite may induce hepatic pathology in vivo.
TL;DR: The metabolism of benzo[a]pyrene is qualitatively similar in tracheobronchial tissues from both humans and animal species in which BP has been experimentally shown to be carcinogenic.
Abstract: The metabolism of benzo[a]pyrene (BP)4by cultured tracheobronchial tissues from different species - human, bovine, hamster, rat and mouse - has been investigated. The total metabolism, as measured by both organic solvent-extractable and water-soluble metabolites of BP, was substantial in the respiratory tract from humans and from animal species susceptible to the carcinogenic action of BP. The ratio of organic-extractable metabolites to water-soluble metabolites was greater than one in hamster, human and C57BI/6N mouse, but less than one in rat, bovine and DBA/2N mouse, suggesting that determination of both activation and deactivation pathways are important in assessing carcinogenic risk of a chemical. Sulphate esters and glutathione conjugates were the major water-soluble metabolites in all animal species; tetrols and diols were the major organic extractable metabolites. The level of trans-7,8-dihydro-7,8-dihydroxybenzo[a]pyrene, the proximate carcinogenic form of BP, was three times higher in C57BI/6N than in DBA/2N mouse trachea. Trans-9,10-dihydro-9,10-dihydroxybenzo[a]pyrene was the major metabolite formed by cultured hamster trachea. The binding levels of BP to cellular DNA were quite similar in all tissues, although slightly higher binding was observed in hamster trachea. Wide inter-individual variation in the binding of BP to DNA was seen in tissues from outbred species. The major BP-DNA adducts in all animal species were formed by interaction of benzo[a]pyrene diol-epoxide with the 2-amino group of deoxyguanosine. Both stereoisomeric forms of (±)-(7β,8α)-dihydroxy-(9α, 10α)-epoxy-7,8,9,10-tetrahydro-benzo[a]pyrene (BPDE I) reacted with deoxyguanosine, the (7R)-form being the most reactive. No difference in the relative distribution of the various adducts was seen between the species except in the CD rat, where BPDE-deoxyadenosine adducts accounted for 20% of the total modification. In cultured hamster trachea the persistence of the different adducts was similar. In conclusion, the metabolism of BP is qualitatively similar in tracheobronchial tissues from both humans and animal species in which BP has been experimentally shown to be carcinogenic.
TL;DR: Four of seven metabolites were identified, and were identical with the main metabolites of aminopyrine, and the main metabolite is the enolglucuronide of N-(2)-demethylpropyphenazone.
Abstract: 1 Propyphenazone 220 mg was administered orally to volunteers. Maximum plasma concentrations between 1.5 microgram/ml and 3.5 micrograms/ml were found 30 min later. After comparable doses plasma concentrations in dog and rabbit were lower. The distribution volumes were 2 l/kg. 2 The major metabolic route of propyphenazone is demethylation. The main urinary metabolite is the enolglucuronide of N-(2)-demethylpropyphenazone. 3 Aminopyrine is rapidly and almost completely absorbed after oral administration. Maximum plasma concentrations of 10 microgram/ml are reached 1.5 h after a 500 mg dose. The biological half-life is 2-3 h, the relative distribution volume 60% on average, and binding to plasma proteins approximately 15%. 4 Unchanged aminopyrine is only excreted in small quantities. The major routes of metabolism are demethylation (4-methylaminoantipyrine and 4-aminoantipyrine) and acylation (4-acetyl and 4-formylaminoantipyrine). There are other biotransformation products. 5 After oral administration of [14C]-dipyrone 480 mg the maximum serum concentration of 13.4 +/- 0.8 microgram/ml occurred at 1-1.5 hours. 6 Dipyrone was not detectable in serum or urine. Four of seven metabolites were identified, and were identical with the main metabolites of aminopyrine.
Journal Article•
TL;DR: The authors found no evidence of the proposed metabolite of furosemide, 2-amino-4-chloro-5-sulfamoylanthranilic acid (CSA) in any of the plasma or urine samples, and conclusively demonstrated CSA to be an analytical artifact.
Abstract: The objectives of this study were to qualitatively and quantitatively compare the metabolism, pharmacokinetics, and bioavailability of furosemide in healthy volunteers after intravenous and oral administration. We also determined the plasma protein binding of furosemide in vivo after iv administration. Nine males received furosemide (Hoechst, 40 mg iv and 80 mg po) in a random crossover fashion. Serial plasma samples were collected over 24 hr. Fluid and electrolyte urinary losses were replaced throughout the study. Furosemide as well as its potential metabolites were measured by a rapid, sensitive, and specific spectrofluorimetric HPLC assay. Total plasma clearance averaged 164 +/- 26 (SD) ml/min, of which 66.2 +/- 6.8% represented renal clearance of unchanged drug. Volume of distribution (steady-state) was 109 +/- 19 ml/kg. These clearance and volume measurements are in good agreement with data previously published by our group. The mean absolute bioavailability of furosemide was 42.8 and 44.0%, as calculated from plasma and urine data, respectively. Protein binding of furosemide in vivo was determined by a spectrofluorimetric HPLC assay and ranged from 98.5 to 99.1%. Approximately 5.5 mg of furosemide was excreted as a glucuronide conjugate after iv dosing and about 5.1 mg after po administration. We found no evidence of the proposed metabolite of furosemide, 2-amino-4-chloro-5-sulfamoylanthranilic acid (CSA) in any of our plasma or urine samples. In addition, we conclusively demonstrated CSA to be an analytical artifact.
TL;DR: Two metabolites were of microfloral origin, as their formation was not observed in germ-free rats but was demonstrated when ellagic acid was incubated in vitro with micro-organisms from rat gastro-intestinal tract.
Abstract: 1. Following oral administration of ellagic acid to the rat, 10% of the dose was excreted as 3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one in urine and faeces. A second metabolite was detected in urine ...
TL;DR: In this article, a catabolic pathway for the isomeric fluorobenzoates was proposed on the basis of key metabolites isolated, and the isoenzymes for total degradation of chlorocatechols, being found during growth with 3-chlorobenzymes or 4-chlorophenol, were not induced in the presence of fluorobenzzoates.
Abstract: 3-Chlorobenzoate-grown cells of Pseudomonas sp. B13 readily cometabolized monofluorobenzoates. A catabolic pathway for the isomeric fluorobenzoates is proposed on the basis of key metabolites isolated. Only 4-fluorobenzoate was utilized and totally degraded after a short period of adaptation. The isoenzymes for total degradation of chlorocatechols, being found during growth with 3-chlorobenzoate or 4-chlorophenol, were not induced in the presence of fluorobenzoates. Correspondingly, only the ordinary enzymes of the benzoate pathway were detected in 4-fluorobenzoate-grown cells. Ring cleavage of 3-fluorocatechol was recognized as a critical step in 3-fluorobenzoate degradation. 2-Fluoro-cis,cis-muconic acid was identified as a dead-end metabolite from 2- and 3-fluorobenzoate catabolism. During 2-fluorobenzoate cometabolism, fluoride is eliminated by the initial dioxygenation.
TL;DR: It was concluded that this role may be in increasing the supply of energy metabolites for milk synthesis, rather than a direct effect on the activity of the mammary gland, where GH is considered to play an important role.
Abstract: 1. Circulating concentrations of some hormones and metabolites and nitrogen balance were measured in lactating beef and dairy cows given daily injections of growth hormone (GH) and were compared to values before injection. Changes in milk yield and composition were recorded in these cows and in additional cows injected with GH fragments. 2. GH, but not GH fragments, raised milk yield while milk composition did not change. GH injection caused a large, rapid increase in the level of the hormone in blood and slower, smaller increases in the concentrations of insulin, prolactin and thyroxine. Blood metabolite levels were unaltered except for a rise in glucose concentration in beef cows during GH injection and a fall in 3-hydroxybutyrate concentration in the same cows after the injections ceased. An increase in N output in milk was partly balanced by a reduction in urinary N so that N retention did not change significantly. 3. GH caused a reduction in food intake in the beef cows. 4. The results are discussed in relation to control of partition of nutrients in the lactating cow, where GH is considered to play an important role. It was concluded that this role may be in increasing the supply of energy metabolites for milk synthesis, rather than a direct effect on the activity of the mammary gland.