4 edition of The effect of mephenytoin on diazepam metabolism in rat and man found in the catalog.
The effect of mephenytoin on diazepam metabolism in rat and man
Timothy V. P. C. Beischlag
Thesis (M.Sc.)--University of Toronto, 1990.
|Series||Canadian theses = Thèses canadiennes|
|The Physical Object|
The present study provides a detailed kinetic analysis of diazepam metabolism by all four known members of the human PC subfamily expressed from their cDNAs in Escherichia coli. Both PC18 and PC19 were found to be low KM diazepam Ndemethylases with apparent KM values of 24 6 4 mM and 21 6 3 mM, respectively. These values closely resemble the low KM component of diazepam . Diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds. No evidence would suggest diazepam alters its own metabolism with chronic administration.  Agents with an effect on hepatic cytochrome P pathways or conjugation can alter the rate of diazepam metabolism.
Some compounds can cause induction of metabolism. It is perhaps better to use the in vitro data to classify compounds into low, medium or high clearance. For most indication high clearance (Rat clearance >70 uL/min/mg protein) compounds would be unsatisfactory and . Given the higher plasma TB clearance and metabolic clearances by N3‐and N7‐demethylation (i.e. 7‐MX and 3‐MX formation) reported in cigarette smokers [ 10] and marked induction of TB metabolism in 3‐methylcholanthrene‐treated rats [ 22], it was assumed that CYP1A2 would be the principal contributor to human hepatic TB metabolism.
For nitrazepam and diazepam, the time to peak was delayed about 1 h in fed condition (P > 005). However it had no effect on their Cmax and AUC. Reaction time of quazepam with light food was prolonged at 4 and 6 h after dosing and its area under the effect–time curve from 0 to 10 h was increased (P. abolizing enzymes allows prediction of the variables affecting drug metabolism, the purpose of the present study was to identify the P enzymes responsible for sufentanil and fentanyl metabolism in human liver microsomes. Microsomal preparations fortified with a reduced nicotinamide-adenine dinucleotide phosphate-generating system were incubated with micro Meter3 H-fentanyl or3 H.
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Ohnhaus EE, Park BK, Colombo JP, Heizmann P. The effect of enzyme induction on diazepam metabolism in man. Br J Clin Pharmacol. Dec; 8 (6)– [PMC free article] Klotz U, Reimann I.
Delayed clearance of diazepam due to cimetidine. N Engl J Med. May 1; (18)–Cited by: EM rats showed markedly higher total CL int of diazepam metabolism than PM due to the large CL int for diazepam p-hydroxylation.
As shown in Figure 4, the major pathways of diazepam metabolism in EM rats are p-hydroxylation and 3-hydroxylation, while PM rats mainly metabolize diazepam at the position of 3-hydroxylation in the low concentration Cited by: 2.
METABOLISM OF DIAZEPAM AND RELATED BENZODIAZEPINES The chemical structures of some benzodiazepines are shown in Fig. These drugs are eliminated from the body mainly by metabolic processes.
Thus, diazepam (DZ) undergoes both N-demethylation and hydroxylation at C-3 to yield a group of pharmaco- logically active metabolites (Fig. 2).Cited by: The metabolism of diazepam has been studied in vitro using microsomal preparations from five human livers.
An HPLC method was developed for the assay of diazepam, its congeners and its metabolites. Various methods for the incorporation of diazepam into the incubation medium were explored.
It was shown that the use of organic solvents or small quantities of hydrochloric acid Cited by: Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that typically produces a calming effect. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, benzodiazepine withdrawal syndrome, muscle spasms, trouble sleeping, and restless legs syndrome.
It may also be used to cause memory loss during certain medical Pregnancy category: AU: C, US: D (Evidence of risk). Hooper WD, Watt JA, McKinnon GE, Reilly PE. Metabolism of diazepam and related benzodiazepines by human liver microsomes. Eur J Drug Metab Pharmacokinet.
Jan-Mar; 17 (1)– [Google Scholar] Beischlag TV, Kalow W, Mahon WA, Inaba T. Diazepam metabolism by rat and human liver in vitro: inhibition by mephenytoin. Xenobiotica. The sedative effects of diazepam are mediated via α1-GABA A receptors in the brain[22,23], and the minimum plasma concentration of diazepam to yield sedative effects is more than ng/mL to ng/mL[18,19].
The pharmacokinetics of diazepam are affected by age[24,25], gender, obesity, liver disease and CYP2C19 genotype status. Possible inhibitory effect of diazepam on the metabolism of zotepine, an antipsychotic drug. Säwe J, Villen T () Importance of genetic factors in the regulation of diazepam metabolism: relationship toS-mephenytoin, but not debrisoquin (Zotepine) in rat, mouse, dog and man.
Arzneimittelforschung – PubMed Google. Benzodiazepines are one of the most commonly prescribed medications to treat anxiety, insomnia, and other conditions in the United States.
1,2 Inapproximately % of US adults ( years old) have used benzodiazepines, and the percentage increases with age.1 Benzodiazepine core chemical structure is composed of diazepine fused to a benzene ring. Purpose: This research investigated the biotransformation of thalidomide by cytochrome P (CYP).
Experimental Design: We used liver microsomes from humans and/or animals and the recombinant specific CYP isozymes to investigate CYP-mediated metabolism of thalidomide. Results: Thalidomide was biotransformed into 5-hydroxythalidomide (5-OH) and diastereomeric 5′-hydroxythalidomide (5′.
Diazepam metabolism has been investigated in cultured hepatocytes from rat, rabbit, dog, guinea pig, and man. The metabolite profile obtained by HPLC analysis of the culture medium indicated that. In this case, if mg is present in the body at time zero, after metabolism, mg may be present at 1 hour and mg at 2 hours (illustrating a maximal clearance of 50 mg/h and no specific half-life).
As drug concentration increases, metabolism shifts from first-order to zero-order kinetics. CYP2C19 is a clinically important enzyme responsible for the metabolism of a number of therapeutic drugs, such as mephenytoin, omeprazole, diazepam.
In studies in which mice and rats were administered Diazepam in the diet at a dose of 75 mg/kg/day (approximately 6 and 12 times, respectively, the maximum recommended human dose [MRHD=1 mg/kg/day] on a mg/m 2 basis) for 80 and weeks, respectively, an increased incidence of liver tumors was observed in males of both species.
The data. Recent panel studies have shown that the large inter‐individual variability in plasma concentrations of proton pump inhibitors can be accounted for by the genetically determined S‐mephenytoin 4′‐hydoxylation polymorphism. 31, 34, 36 However, the magnitude of the contribution of CYP2C19‐mediated metabolism of proton pump inhibitors.
Mephenytoin is a heterocyclic organic compound with anticonvulsant property. Although the mechanism of action is not well established, mephenytoin potentially promotes sodium efflux from neurons in motor cortex, and stabilizes the threshold against hyperexcitability caused by excessive stimulation.
Thus this agent reduces the membrane sodium gradient and prevents cortical seizure signal spreading. As shown in Figure 4, the major pathways of diazepam metabolism in EM rats are p ‐hydroxylation and 3‐hydroxylation, while PM rats mainly metabolize diazepam at the position of 3‐hydroxylation in the low concentration range.
4 Effect of substrate concentrations on diazepam metabolism in liver microsomes from EM and PM Wistar rats: The. PubMed:Diazepam metabolism by rat and human liver in vitro: inhibition by mephenytoin.
PubMed: The effects of felodipine on the pharmacokinetics of diazepam. PubMed: Comparative metabolism of clinically important precursors of N-desmethyldiazepam using phenobarbitone-pretreated rat. Polymorphic metabolism of mephenytoin in man: pharmacokinetic interaction with a co-regulated substrate, mephobarbital.
Clin Pharmacol Ther. Jun; 39 (6)– [Google Scholar] James R, Küpfer A, Villeneuve JP, Branch RA. Induction of drug-metabolizing enzymes by the enantiomers of normephenytoin in the rat. Drug Metab Dispos. In studies in which mice and rats were administered diazepam in the diet at a dose of 75 mg/kg/day (approximately 6 and 12 times, respectively, the maximum recommended human dose [MRHD = 1 mg/kg/day] on a mg/m² basis) for 80 and weeks, respectively, an increased incidence of liver tumors was observed in males of both species.
Incidence of S-mephenytoin hydroxylation deficiency in a Korean population and the interphenotypic differences in diazepam The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans Identification of glucocorticoid-inducible cytochromes P in the intestinal mucosa of rats and man.
J.A physiologically based pharmacokinetic model for diazepam disposition was developed in the rat, incorporating anatomical, physiological, and biochemical parameters, i.e., tissue volume, blood flow rate, serum free fraction, distribution of diazepam into red blood cells, drug metabolism and tissue-to-blood distribution ratio.
The serum free fraction of diazepam was determined by equilibrium.The displacing effect of a fatty acid on the binding of diazepam to human serum albumin. Tsutsumi, E., Inaba, T., Mahon, W.
A. Biliary elimination of diazepam in man.