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  • 1
    Electronic Resource
    Electronic Resource
    Reduction of aflatoxin B1 to aflatoxicol (1977)
    s.l. : American Chemical Society
    Journal of agricultural and food chemistry 25 (1977), S. 437-438 
    Details
    ISSN: 1520-5118
    Source: ACS Legacy Archives
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Process Engineering, Biotechnology, Nutrition Technology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/jf60210a052
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  • 2
    Electronic Resource
    Electronic Resource
    Difference in metabolic profile of potassium canrenoate and spironolactone in the rat: Mutagenic metabolites unique to potassium canrenoate (1988)
    Springer
    Archives of toxicology 61 (1988), S. 201-212 
    Details
    ISSN: 1432-0738
    Keywords: Potassium canrenoate ; Spironolactone ; Metabolism (rat in vivo and in vitro) ; Mutagenic metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The metabolic fates of potassium canrenoate (PC) and spironolactone (SP) were compared for the rat in vivo and in vitro. Approximately 18% of an in vivo dose of SP was metabolized to canrenone (CAN) and related compounds in the rat. In vitro, 20–30% of SP was dethioacetylated to CAN and its metabolites by rat liver 9000 g supernatant (S9). Thus, the major route of SP metabolism is via pathways that retain the sulfur moiety in the molecule. PC was metabolized by rat hepatic S9 to 6α, 7α- and 6β, 7β-epoxy-CAN. The β-epoxide was further metabolized to its 3α- and 3β-hydroxy derivatives as well as its glutathione (GSH) conjugate. Both 3α- and 3β-hydroxy-6β, 7β-epoxy-CAN were shown to be direct acting mutagens in the mouse lymphoma assay, whereas 6α, 7α- and 6β, 7β-epoxy-CAN were not. These mutagenic metabolites, their precursor epoxides and their GSH conjugates were not formed from SP under identical conditions. The above findings appear to be due to inhibition of metabolism of CAN formed from SP by SP and/or its S-containing metabolites, since the in vitro metabolism of PC by rat hepatic microsomes was appreciably reduced in the presence of SP. The hypothesized mechanism(s) for this inhibition is that SP and its S-containing metabolites specifically inhibit an isozyme of hepatic cytochrome P-450 or SP is a preferred substrate over PC/CAN for the metabolizing enzymes. Absence of the CAN epoxide pathway in the metabolism of SP provides a possible explanation for the observed differences in the toxicological profiles of the two compounds.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00316635
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  • 3
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of a Novel Antiarrhythmic Drug, Actisomide (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 427-433 
    Details
    ISSN: 1573-904X
    Keywords: actisomide ; species-dependent absorption ; pH effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of a novel antiarrhythmic drug, actisomide, were examined in the rat, dog, monkey, and human. The terminal half-life of actisomide was similar (1.15–1.89 hr) across species, regardless of dose. The total plasma clearance was higher in the monkey (13.5–16.4 mL/min/kg) than in the dog (9.01–9.32 mL/min/kg), rat (8.6–9.8 mL/min/kg), or human (6.79 ± 1.07 mL/min/kg). Excretion of the parent drug was higher in urine than in feces in the dog and rat, whereas in the monkey and human, urinary and fecal excretions of actisomide were similar. In humans, atypical plasma concentration–time curves with double peak concentrations were observed following oral doses. Systemic availability of actisomide was higher in the dog than in the rat, monkey, and human. Further, the systemic availability appeared to increase with dose in the rat and monkey. The species-dependent systemic availability appeared to be due primarily to species-dependent absorption of actisomide, and not to species-dependent first-pass metabolism, biliary excretion, and/or renal elimination. The absorption of actisomide in the rat and its in vitro uptake in CaCo-2 cells were pH dependent. The higher systemic availability of actisomide observed in the dog may be due partly to the higher pH in the gastrointestinal (GI) tract of the dog. However, the pH differences in the GI tract of the different species alone did not appear to be enough to explain the difference in systemic availability of actisomide.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018900725050
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  • 4
    Electronic Resource
    Electronic Resource
    Species Dependent Esterase Activities for Hydrolysis of an Anti-HIV Prodrug Glycovir and Bioavailability of Active SC-48334 (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1158-1164 
    Details
    ISSN: 1573-904X
    Keywords: glycovir ; SC-48334 ; esterase activities ; species difference ; in vitro-in vivo correlation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The in vitro fate of an ester prodrug, glycovir, was studied to determine if the species differences in the bioavailability of pharmacologically active SC-48334 observed after glycovir administration and not observed after SC-48334 administration is due to species differences in ester hydrolysis rate or species differences in absorption of the prodrug itself, and to determine the site(s) of ester hydrolysis which contributes most to species differences in the bioavailability of SC-48334 if any. Methods. Glycovir was incubated with small intestinal mucosa, liver S9 fractions, whole blood, red blood cells (RBC) and plasma of the rat, dog, monkey (cynomolgus and rhesus) and man, and glycovir concentrations were determined by HPLC. Results. The relative bioavailabilities of SC-48334 after prodrug administration to the rat, dog, monkey and man were 99,15, 42 and 37%, respectively. After SC-48334 administration, SC-48334 was rapidly and similarly well absorbed in all species. The hydrolysis rate in the small intestinal mucosa was well correlated with the relative bioavailability of SC-48334 after prodrug administration. Among different species the hydrolysis rate of glycovir in liver S9 fractions, blood, RBC and plasma did not parallel those in the mucosa of the small intestine. Conclusions. The species differences in bioavailability of SC-48334 with the prodrug were due to species differences in hydrolysis rates of the prodrug in small intestinal mucosa. The monkey was a good animal model for prediction of esterase activity in human small intestine and relative bioavailability in man.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016259826037
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  • 5
    Electronic Resource
    Electronic Resource
    Mechanisms of Food Effects of Structurally Related Antiarrhythmic Drugs, Disopyramide and Bidisomide in the Rat (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 1030-1038 
    Details
    ISSN: 1573-904X
    Keywords: food effect ; disopyramide ; bidisomide ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine whether the rat is a good animal model for the food effects observed with bidisomide but not with the structurally similar antiarrhythmic drug, disopyramide in man and to explore a reason for the differences in the food effects of these compounds. Methods. The following effects on the absorption of bidisomide and/ or disopyramide were examined in the rat: Food effects, gastrointestinal transit time under fasting and nonfasting conditions, pH effects, hypertonic solution effect of NaCl and glucose, bile effects, permeability, inhibitory effects by Gly, Gly-Gly, Gly-Pro, glucose and mannitol and drug binding to food. Results. Remarkable food effects were observed with bidisomide but not with disopyramide. There was no difference in the GI transit time with and without food. The pH effect with and without food was similar. Effect of salt concentrations on bidisomide and disopyramide was similar. There was no bile effect on absorption of both compounds. Binding of bidisomide and disopyramide to food was similarly low. The apparent permeability of bidisomide was much lower than disopyramide especially in the ileum and its absorption was more inhibited by Gly, Gly-Gly and Gly-Pro. Conclusions. In the rat, as previously seen in humans, the food effect was observed with bidisomide but not with disopyramide. This difference was in part due to both lower intestinal permeability of bidisomide compared to disopyramide and greater inhibition of absorption by the amino acid, Gly and the dipeptides, Gly-Gly and Gly-Pro.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1012101311826
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  • 6
    Electronic Resource
    Electronic Resource
    Mechanism of Compound- and Species-Specific Food Effects of Structurally Related Antiarrhythmic Drugs, Disopyramide and Bidisomide (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 429-433 
    Details
    ISSN: 1573-904X
    Keywords: food effect ; bidisomide ; disopyramide ; dog ; species difference
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine mechanism of food effects observed with bidisomide but not with the structurally similar drug, disopyramide. Methods. Food effect studies of bidisomide and disopyramide were conducted with and without a standardized high fat meal in healthy subjects and in the dog. Intestinal metabolism of disopyramide and absorption of the metabolites were examined after oral administration of the drug to the dogs with portal vein canula implanted. Effects of food or a mixture of amino acids on metabolism of [14C]disopyramide were examined after intraportal infusion of the drug with and without high fat meal and after drug infusion into portal vein with the amino acid mixture, respectively. Results. The systemic availability of bidisomide was markedly reduced with food in humans, whereas the systemic availability of disopyramide did not change notably. In the dog, the systemic availability of bidisomide was also reduced with food. The systemic availability of disopyramide did not change with food. This was due to the fact that reduction in absorption was compensated by reduction of metabolism. There was no evidence for reduction in hepatic and intestinal metabolism with food. Conclusions. The apparent reduction in disopyramide metabolism with food may be due to an increase in colonal and /or lymphatic absorption. Food effects on the apparent systemic availability of bidisomide and disopyramide in the dog were similar to those in the rat. However, there was substantial species difference in the mechanism of food effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011976331738
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