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At least 433 records · Page 24Linked to original sources
PubMed1989

Zonal compartmentation of perfused rat liver: plasma reappearance of rhodamine B explained.

Rhodamine B (RB) fluorescence reappears in perfusion medium of a cyclically perfused rat liver after a rapid initial removal phase. At the same time the compound redistributes in the liver from acinar zone 1 toward zone 3. By analysis of the metabolic profile of RB, and by inhibition of glucuronidation (the main metabolic route) with salicylamide, we show in this paper that formation and secretion of RB-conjugates from liver into perfusate is not involved in the reappearance and redistribution phenomena. We therefore sought the explanation in a kinetic model, in which the acinar heterogeneity of the liver was simulated by several sequential liver compartments. Most kinetic parameters we used in the simulation were calculated from previous experiments with RB (Braakman et al., Hepatology 7: 849-855, 1987). This led to an accurate simulation of the measured RB curves in bile, medium and the acinar zones of the liver. In this study we show that a secondary rise in medium concentration of an injected compound is not necessarily caused by metabolism, but can be easily explained by considering the liver a sequence of compartments, instead of one well-stirred compartment. The conditions for the reappearance as well as for the intrahepatic redistribution are: a fast uptake into the liver, combined with a fast sinusoidal secretion and a slow biliary excretion of the injected substance.

Animals↗
PubMed1986

Sulfate conjugation in drug metabolism: role of inorganic sulfate.

Conjugation with sulfate is a major pathway for the biotransformation of phenolic drugs in humans and many animal species. It is a process of limited capacity; the extent of sulfate conjugate formation and the metabolic clearance of drugs subject to conjugation with sulfate depend therefore on the dose, the dosage form, the route of administration, and the rate and duration of administration as well as on the pharmacokinetic parameters of competing processes. The effect of these variables is exemplified by the pharmacokinetics of salicylamide and acetaminophen in humans and rats. In our experience so far, the proximate cause of the nonlinear pharmacokinetics of sulfate conjugation of phenolic drugs is the limited availability and consequent depletion of inorganic sulfate. When this is prevented by direct or indirect (via sulfate donors such as N-acetylcysteine) repletion, the saturability of phenol sulfotransferase (EC 2.8.2.1) activity can become evident. The major mechanism of inorganic sulfate homeostasis is nonlinear renal clearance, which is due largely to saturable renal tubular reabsorption. Systemic depletion of inorganic sulfate secondary to utilization of this anion for the sulfation of drugs affects the availability of sulfate in the central nervous system and may, therefore, modify the disposition of certain neurotransmitters and other endogenous substances that are subject to sulfate conjugation.

Acetaminophen↗
PubMed1985

Protection against toxic redox cycles between benzo(a)pyrene-3,6-quinone and its quinol by 3-methylcholanthrene-inducible formation of the quinol mono- and diglucuronide.

Cytotoxic effects of quinones are thought to be mediated by redox cycles between quinones and quinols whereby reactive oxygen species are generated. The role of glucuronidation in preventing these toxic redox cycles was investigated by using benzo(a)pyrene-3,6-quinone and isolated rat hepatocytes or Reuber hepatoma cells (H4IIE). Inhibition of quinol glucuronidation by salicylamide enhanced quinone-dependent oxygen uptake and cytotoxicity. Conjugation of benzo(a)pyrene-3,6-quinol was shown to proceed via the 6-monoglucuronide to the diglucuronide. Diglucuronide formation was low in hepatocytes from untreated controls and phenobarbital-treated rats. However, it was highly stimulated (26-fold) in hepatocytes from 3-methylcholanthrene-treated rats and was also high in Reuber hepatoma cells. Kinetic analysis with liver microsomes indicated that 3-methylcholanthrene-stimulated glucuronidation was due to an increased Vmax of UDP-glucuronosyltransferase which was enhanced 10- and 40-fold or mono- and diglucuronide formation, respectively. These findings suggest that the investigation of quinol glucuronidation (in particular the formation of benzo(a)pyrene-3,6-quinol diglucuronide) is a most useful probe for the 3-methylcholanthrene-inducible isoenzyme(s) of UDP-glucuronosyltransferase. Moreover, this isoenzyme may be particularly suited to protect against toxic redox cycles between benzo(a)pyrene quinones and quinols.

Animals↗
PubMedDate not supplied

Inhibition of morphine glucuronidation by oxazepam in human fetal liver microsomes.

Uridine diphosphoglucuronyltransferase activity toward morphine was measured in vitro in preparations of human fetal liver microsomes. The inhibition of the glucuronidation of morphine was studied at concentrations of morphine and uridine diphosphoglucuronic acid of 3 and 15 mM, respectively. Oxazepam inhibited the reaction by about 50% at concentration of 0.3 mM. The inhibition was almost complete when the concentration was 3 mM, i.e., the same as for morphine. Salicylamide was considerably less potent as an inhibitor of morphine glucuronidation with an almost 100-fold difference in potency as compared to oxazepam. Lineweaver-Burk plots of the inhibition data revealed that oxazepam exerts a competitive type of inhibition with an apparent Ki value of 0.2 mM.

Dose-Response Relationship, Drug↗
PubMedDate not supplied

Inhibition of human red blood cell N-acetyltransferase.

Acetanilide and derivatives of benzoic acid, benzamide, salicylic acid, and salicylamide were tested as inhibitors of p-aminobenzoic acid N-acetyltransferase partially purified from peripheral blood of three rapid and two slow dapsone acetylator human volunteers. The 50% inhibition point of these compounds does not provide a kinetic basis for differentiating the rapid and slow dapsone acetylator phenotypes.

4-Aminobenzoic Acid↗
PubMed1993

The development of dopamine D2-receptor selective antagonists.

This paper reviews the development of 2,6-dioxygenated benzamides such as remoxipride and various salicylamides (raclopride, eticlopride) into other types having a 5,6-dioxygenated benzamide moiety. The structural, conformational and stereochemical aspects on the structure-activity relationships are discussed. The three side chain classes (S)-2-pyrrolidinylmethyl-, (R)-2-pyrrolidinylmethyl- and 4-piperidinylbenzamides have different requirements on aromatic substituents and side chain conformations. Besides, the latter two types demand lipophilic nitrogen substituents (arylalkyl) for dopamine D2 receptor affinity. This indicates that they have different pharmacophoric requirements that might prove useful in investigations on dopamine D2 receptor subtypes. The 3-substituted 5,6-dimethoxysalicylamides (e.g. FLB 463 and NCQ 298) and the 3-substituted 5,6-dimethoxybenzamides (e.g. FLB 457 and NCQ 219) constitute highly potent and selective dopamine D2 antagonists in vitro as well as in vivo. Both types of benzamides have been developed as radioligands for receptor binding (125I, 3H), PET (11C, 18F) and SPECT (123I) studies which fully take advantage of the favourable properties. Thus, NCQ 298, NCQ 115, FLB 457 and NCQ 616 are such potent and selective ligands, which are suitable for further receptor characterization and studies on dopamine D2 mediated responses.

Animals↗
PubMed1999

High-resolution structures of scytalone dehydratase-inhibitor complexes crystallized at physiological pH.

Scytalone dehydratase is a molecular target of inhibitor design efforts aimed at preventing the fungal disease caused by Magnaporthe grisea. A method for cocrystallization of enzyme with inhibitors at neutral pH has produced several crystal structures of enzyme-inhibitor complexes at resolutions ranging from 1.5 to 2.2 A. Four high resolution structures of different enzyme-inhibitor complexes are described. In contrast to the original X-ray structure of the enzyme, the four new structures have well-defined electron density for the loop region comprising residues 115-119 and a different conformation between residues 154 and 160. The structure of the enzyme complex with an aminoquinazoline inhibitor showed that the inhibitor is in a position to form a hydrogen bond with the amide of the Asn131 side chain and with two water molecules in a fashion similar to the salicylamide inhibitor in the original structure, thus confirming design principles. The aminoquinazoline structure also allows for a more confident assignment of donors and acceptors in the hydrogen bonding network. The structures of the enzyme complexes with two dichlorocyclopropane carboxamide inhibitors showed the two chlorine atoms nearly in plane with the amide side chain of Asn131. The positions of Phe53 and Phe158 are significantly altered in the new structures in comparison to the two structures obtained from crystals grown at acidic pH. The multiple structures help define the mobility of active site amino acids critical for catalysis and inhibitor binding.

Base Sequence↗
PubMed1996

Studies on the selection of new matrices for ultraviolet matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

A new group of compounds has been successfully tested as matrices for ultraviolet matrix-assisted laser desorption/ionization mass spectrometry (UV-MALDI MS). Several new matrices for UV-MALDI MS have been found by choosing, as potential matrices, compounds that perform an intramolecular proton transfer along an intramolecular H-bond under UV irradiation. Compounds of this type are, for example, salicylamide, salicylanilide, several ortho-hydroxyacetophenones and ortho-hydroxybenzophenones. The matrix activity of these compounds is compared to the corresponding meta- and para-isomers and to the matrix activity of such well known matrices as 2,5-dihydroxybenzoic acid and 2,4,6-trihydroxyacetophenone. It was found that meta- and para-substituted hydroxycarbonyl compounds show either a significantly lower or no matrix activity compared with the ortho isomers.

Indicators and Reagents↗
PubMed1989

[Determination of the protein binding of drugs by continuous ultrafiltration. 9. Comparison of the binding of nonsteroid antirheumatics to human serum albumin and their interaction with phenprocoumon].

Binding to HSA has been determined for diflunisal (alpha = 0.03%), diclofenac (0.09), ibuprofen (0.10), bumadizone (0.11), ketoprofen (0.14), oxyphenbutazone (0.28), indomethacin (0.39), mofebutazone (0.57), tenoxicam (0.59), piroxicam (0.91), salicylic acid (1.00), o-carbamoylphenoxyacetic acid (11.58) and salicylamide (24.91). The free concentration of phenprocoumon was raised by diflunisal up to 35% in a dose dependent manner. Ibuprofen and piroxicam did not show significant effects. It is concluded that diflunisal is bound only slightly to the phenoprocoumon binding site of HSA while ibuprofen has no affinity to this part of the albumin molecule.

4-Hydroxycoumarins↗
PubMed1977

Synthesis of some dibenzazepines of possible therapeutic interest.

Among the hypotensive drugs are the N-alkyldibenz[c,e]-azepines. A representative of this class is 6-allyl-6,7-dihydro-5H-dibenz[c,e]azepine (azapetine). The present investigation involved the preparation of a new series of N-[6,7-dihydro-5H-dibenz[c,e]azepin-6-yl] acid amides namely; acetamide, benzamide, phehyl acetamide, salicylamide and p-hydroxybenzamide derivatives. Another new series of N-[6,7-dihydro-5H-dibenz[c,e]azepin-6-yl]-N-alkyl (or aryl) thioureas was prepared namely ethyl, isopropyl, butyl, cyclohexyl, benzyl, phenyl and o-tolyl thiourea derivatives. IR spectra of the two series of compounds were investigated.

Antihypertensive Agents↗
PubMed1981

Inhibition of mucopolysaccharide sulfation.

A method of measuring the inhibition of sulfation in mucopolysaccharides employed the coupled enzyme system of Wortman. This procedure utilized the phenol and mucopolysaccharide sulfotransferases of beef cornea extract. Compounds tested against this system included amino acids, salicylates, 2-mercaptoethylamine and a derivative, heterocyclic ethanethiosulfuric acids, arylsulfonamidoethanethiosulfates, and several other compounds. In general, the salicylates and thiosulfates were inhibitory, with sodiumm 2-(4-acetamidobenzenesulfonamido)-ethanethiosulfate being the most inhibitory and 2-mercaptoethylguanidine trithiocarbonic acid the second most inhibitory. Salicylamide and allopurinol, which have been employed in kidney stone therapy, were inhibitors. Kidney stones have a mucopolysaccharide sulfate matrix, which is involved in their growth.

Animals↗
PubMed1981

Simultaneous high-performance liquid chromatographic determination of theophylline, ephedrine hydrochloride, and phenobarbital in tablets.

A rapid reversed-phase high-performance liquid chromatographic (HPLC) method was developed for the simultaneous assay of theophylline, ephedrine hydrochloride, and phenobarbital in a tablet matrix. A methanolic extract of the powdered sample containing salicylamide as the internal standard was injected into the chromatograph. The HPLC system used methanol-0.007 M monobasic potassium phosphate (37:63, pH 2.3) as the mobile phase. Detection was at 254 nm, and quantitation was based on the drug-internal standard peak area ratio. This ratio was linear over a concentration range of 20.9-83.5 microgram of theophylline, 4-15.9 microgram of ephedrine hydrochloride, and 1.3-5.1 microgram of phenobarbital. Overall recoveries (+/- SD) from three synthetic tablets were: theophylline, 99.8 +/- 1.3%; ephedrine hydrochloride, 100.2 +/- 0.6%; and phenobarbital, 99.4 +/- 0.7%. The method was compared to the compendial method and also was applied to the assay of commercial tablets containing these three active ingredients. The proposed method is applicable to the assay of individual tablets.

Chromatography, High Pressure Liquid↗
PubMed1982

Application of the ammonia gas-sensing electrode: determination of drugs having a carboxyamide group by decomposition with acid.

A simple potentiometric method for the determination of drugs having a carboxyamide group is described. Ethenzamide, niacinamide, pyrazinamide, or salicylamide was refluxed with 20% HCl and the carboxyamide was hydrolyzed. The ammonia evolved at a pH greater than 11 and was determined without separation from the decomposition solution using an ammonia gas-sensing electrode. A linear calibration plot was obtained with drugs in the range of 2 x 10(-5) - 1 x 10(-2) M. This method was applied to the analysis of injection and powder-containing auxiliary compounds.

Amides↗
PubMed1991

Analysis of rat lymphocyte activation of benzo[a]pyrene, 2-acetylaminofluorene, and several of their metabolites to mutagenic and DNA-damaging species in vitro.

Rat lymphocytes are a potentially useful and convenient cell system for monitoring the genotoxic effects of chemicals in vivo, but little is known about the ability of these cells to metabolize promutagens to genotoxic species. In this study, Fischer 344 rat lymphocytes were treated in vitro with benzo[a]pyrene (BaP), 2-acetylaminofluorene (2-AAF), and several of their metabolites, and DNA damage was measured using nucleoid sedimentation analysis. Of the BaP derivatives, BaP 4,5-oxide and BaP 7,8-diol-9, 10-epoxide decreased lymphocyte nucleoid sedimentation, whereas BaP and BaP 7,8-dihydrodiol had little effect. Among the 2-AAF derivatives, N-acetoxy-2-AAF, N-hydroxy-2-AAF, and N-hydroxy-2-aminofluorene damaged rat lymphocyte nucleoids, whereas 2-AAF, 2-aminofluorene, and fluorene produced little detectable damage. The decrease in nucleoid sedimentation produced by N-hydroxy-2-AAF was not inhibited by paraoxon, salicylamide, or 2-aminofluorene, whereas paraoxon inhibited damage produced by N-acetoxy-2-AAF. In co-culture assays, rat lymphocytes increased the mutagenicity of N-hydroxy-2-AAF in Salmonella typhimurium strain TA98, but mediated little or no mutagenic response with BaP, BaP 7,8-dihydrodiol, and 2-AAF. Also, human lymphocytes, but not rat lymphocytes, mediated a positive mutagenic response with BaP 7,8-dihydrodiol in Chinese hamster ovary UV5 cells. Although rat lymphocytes may metabolize certain proximal genotoxic chemicals to DNA-damaging species (e.g., N-hydroxy-2-AAF), these data suggest that in vivo lymphocyte DNA damage is more likely to result from lymphocytes encountering reactive chemical derivatives produced by other cells. It is also clear that differences exist between the ability of human and rat lymphocytes to activate promutagens, and this may impact on the use of the rat model to predict the genotoxicity of chemicals in humans.

2-Acetylaminofluorene↗
PubMed1978

Correlation between in vitro and in vivo drug metabolism rate: oxidation of ethoxybenzamide in rat.

In vitro and in vivo correlations of the microsomal oxidation of drugs were examined, using ethoxybenzamide as a model drug. Ethoxybenzamide disappearance time course from rat plasma in vivo was analyzed by a two-compartment model assuming a Michaelis-Menten type elimination process. Ethoxybenazmide oxidation in vitro was measured by the appearance rate of salicylamide in rat liver microsomal suspension. Parameters obtained were Vmax = 3.46 and 3.77 mumoles/min/kg body weight and Km = 0.378 and 0.192 mM, in vitro and in vivo, respectively.

Animals↗
PubMed2003

Nematocidal activity of nitazoxanide in laboratory models.

The nematocidal activity of a broad-spectrum antiparasitic agent, nitazoxanide [( N-(5-nitrothiazol-2-gammal)salicylamide; NTZ], was evaluated in both in vitro and in vivo models using Caenorhabditis elegans, Heligmosomoides polygyrus and Trichinella spiralis. In vitro, NTZ (100 muM) exhibited a low activity against C. elegans and had no effect on embryonation and hatching of H. polygyrus eggs. At concentrations of 100 and 50 muM, the inhibition of excretion/secretion of acetylcholinesterase and acid phosphatase of adult H. polygyrus by NTZ was variable. The in vitro effects of mebendazole (5 muM), albendazole (1 muM) and levamisole (10 muM) were superior to those of NTZ. In mice, NTZ at 1 g/kg proved to be inactive against preadults of T. spiralis whereas mebendazole at 10 mg/kg reduced the worm burden by up to 83%. NTZ at 1 g/kg per day for 3 consecutive days showed a low activity against adults of H. polygyrus (21% reduction). Levamisole, at a single dose of 10 mg/kg, reduced the worm burden by up to 89.9%. The results of this study suggest that NTZ would not have met criteria of a candidate compound.

Animals↗
PubMed1983

Antipyretic analgesics and the allergic patient.

Recent studies of idiosyncratic reactions to analgesics have revealed several clinical patterns with different pathogeneses. In the common type of asthma precipitated by aspirin, inhibition of cyclooxygenase leads to disturbances in the metabolism of arachidonic acid. Drugs that precipitate possibly life-threatening bronchoconstriction and are absolutely contraindicated in patients with aspirin-induced asthma include indomethacin, mefenamic acid, flufenamic and meclofenamic acids, ibuprofen, fenoprofen, ketoprofen, naproxen, diclofenac, amidopyrine, noramidopyrine, phenylbutazone, flumizole, and ditazol. If necessary, patients with aspirin-induced asthma can safely take, even on a long-term basis, salicylamide, dextropropoxyphene, benzydamine, guaiacolic ester of salicylic acid, and chloroquine. In some patients with urticaria/angioedema, symptoms are due to inhibition of cyclooxygenase by analgesics; in others, the cause may be impurities in commercial preparations of aspirin; and in still others, the mechanisms remain unknown.

Acute Disease↗