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Metabolite Data (metabolite + data)
Selected AbstractsEffect of mercury and Gpi-2 genotype on standard metabolic rate of eastern mosquitofish (Gambusia holbrooki),ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 4 2001Christopher Paul Tatara Abstract Previous studies demonstrated differential mortality among mosquitofish of different Gpi-2 genotypes during acute mercury and arsenate exposures. Mercury-exposed mosquitofish also had Gpi-2 genotype-specific differences in glycolytic and Krebs cycle metabolite pools. The mortality and metabolite data suggested that mosquitofish bearing specific Gpi-2 genotypes might differ in metabolic efficiency, with less efficient Gpi-2 genotypes having higher standard metabolic rates (SMRs) and shorter times to death during acute mercury exposure. Effect of Gpi-2 genotype on SMR was assessed with a factorial arrangement of six Gpi-2 genotypes and two exposure sequences (Control , Control; Control , 100 ,g/L Hg). The SMRs were estimated by measuring oxygen consumption using an indirect, closed-circuit, computer-controlled respirometer. A 48-h exposure to 100 ,g/L of mercury resulted in a 16.7% elevation of SMR above control levels (p = 0.001). The Gpi-2 genotype and the number of heterozygous loci per individual had no significant effect on SMR in mercury-exposed mosquitofish. The experimental results do not support the hypothesis that Gpi-2 genotype-specific differences in glycolytic and Krebs cycle metabolite pools and mortality in mosquitofish exposed to mercury are associated with differences in SMR. [source] Formed and preformed metabolites: facts and comparisonsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2008Professor K. Sandy Pang The administration of metabolites arising from new drug entities is often employed in drug discovery to investigate their associated toxicity. It is expected that administration of metabolites can predict the exposure of metabolites originating from the administration of precursor drug. Whether exact and meaningful information can be obtained from this has been a topic of debate. This communication summarizes observations and theoretical relationships based on physiological modelling for the liver, kidney and intestine, three major eliminating organs/tissues. Theoretical solutions based on physiological modelling of organs were solved, and the results suggest that deviations are expected. Here, examples of metabolite kinetics observed mostly in perfused organs that did not match predictions are provided. For the liver, discrepancies in fate between formed and preformed metabolites may be explained by the heterogeneity of enzymes, the presence of membrane barriers and whether transporters are involved. For the kidney, differences have been attributed to glomerular filtration of the preformed but not the formed metabolite. For the intestine, the complexity of segregated flows to the enterocyte and serosal layers and differences in metabolism due to the route of administration are addressed. Administration of the metabolite may or may not directly reflect the toxicity associated with drug use. However, kinetic data on the preformed metabolite will be extremely useful to develop a sound model for modelling and simulations; in-vitro evidence on metabolite handling at the target organ is also paramount. Subsequent modelling and simulation of metabolite data arising from a combined model based on both drug and preformed metabolite data are needed to improve predictions on the behaviours of formed metabolites. [source] Enrofloxacin and marbofloxacin in horses: comparison of pharmacokinetic parameters, use of urinary and metabolite data to estimate first-pass effect and absorbed fractionJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2006M. PEYROU Enrofloxacin and marbofloxacin are two veterinary fluoroquinolones used to treat severe bacterial infections in horses. A repeated measures study has been designed to compare their pharmacokinetic parameters, to investigate their bioavailability and to estimate their absorbed fraction and first-pass effect by using plasma, urinary and metabolite data collected from five healthy mares. Clearance and Vd(ss) were greater for enrofloxacin (mean ± SD = 6.34 ± 1.5 mL/min/kg and 2.32 ± 0.32 L/kg, respectively) than for marbofloxacin (4.62 ± 0.67 mL/min/kg and 1.6 ± 0.25 L/kg, respectively). Variance of the AUC0-inf of marbofloxacin was lower than that for enrofloxacin, with, respectively, a CV = 15% and 26% intravenously and a CV = 31% and 55% after oral administration. Mean oral bioavailability was not significantly different between marbofloxacin (59%) and enrofloxacin (55%). The mean percentage of the dose eliminated unchanged in urine was significantly higher for marbofloxacin (39.7%) than that for enrofloxacin (3.4%). Absorbed fraction and first-pass effect were only determinable for enrofloxacin, whereas the percentage of the dose absorbed in the portal circulation was estimated to be 78% and the fraction not extracted during the first pass through the liver was 65%. Consequently, the moderate observed bioavailability of enrofloxacin appears to be mainly caused by hepatic first-pass effect. [source] The New European Medicines Agency Guideline on the Investigation of BioequivalenceBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2010José Augusto Guimarães Morais Several new features have been added to this guideline, as well as changes aimed at improving the clarity of the guidance provided. The first issue to be addressed was to limit the scope of the guideline to bioequivalence studies for immediate release dosage forms with systemic action. Therefore, the guideline refers to bioequivalence alone. Moreover, the new definition of Generic Medicinal Product has been incorporated. Clearer guidance covering more specific cases is now given on sections such as: fed/fasting conditions, use of metabolite data, enantiomers and strength to be used in the bioequivalence study. Steady-state design is now restricted and other designs, such as parallel group design, replicate design and two-stage design, are now incorporated in a more explicit form. New practical guidance on Highly Variable Drug Products and Narrow Therapeutic Index Drugs has been incorporated. The possibility for a biowaiver based on the Biopharmaceutics Classification System is now more explicit for Class I drugs and can be extended to Class III drugs under restricted conditions. We are aware that the initial goal of providing a very specific and clear guidance on these issues has not been entirely achieved, mainly because it is almost impossible to cover all individual cases and predict every possible situation that may arise. Demonstration of bioequivalence will still require in many instances a case by case approach. [source] | ||||||||||