Oxidative metabolites pharmacology

Zopiclone is available as a racemic mixture. Zopiclone, 7.5 mg administered orally at nighttime, is rapidly absorbed. It has a bioavailability of approximately 75 % and a time of occurrence of maximum plasma concentration (Cmax) of 1.6 hours [22, 23], The compound undergoes oxidation to the N-oxide metabolite, which is pharmacologically active, and demethylation to the inactive N-demethyl-zopiclone (Tab. 2). The elimination half-life (ti/2) of zopiclone and its active metabolite ranges from 3.5 to 6.0 h [24],... 

Jewell H, Maggs JL, Harrison AC et al (1995) Role of hepatic metabolism in the bioactivation and detoxication of amodiaquine. Xenobiotica 25 199-217 follow DJ, Mitchell JR, Zampaglione N et al (1974) Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3, 4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 11 151-169... 

A major route of metabolism for (67) and (73) is oxidation at the C9 position to form hydroxymethyl and carboxyl metabolites. The hydroxymethyl metabolites are potent CBi agonists with pharmacological profiles similar to the parent compounds, while the carboxy metabolites have reduced activity [115] the 9-carboxy analogue of (73) does not bind to the CBi receptor [93]. 

Metabolism of fenvalerate proceeds by way of oxidation and hydrolysis to produce metabolites considered pharmacologically inactive or inferior to the parent compound. Insects and fish are extremely susceptible to fenvalerate when compared to mammals and birds. Interspecies differences are associated with rates of metabolism, excretion, absorption, esterase activity, and neurosensitivity. 

Amine oxides are readily reduced back to tertiary amines (Fig. 5.9). There are few drugs that are amine oxides, but there are many drugs that are tertiary amines and amine oxides are common metabolites. The amine oxide is often pharmacologically inactive however, because they are readily reduced back to tertiary amines, amine oxides can act as a buffer to the concentration of the tertiary amine. 

Sutton, D., Butler, A.M., Nadin, L. and Murray, M. (1997) Role of CYP3A4 in human hepatic diltiazem N-demethylation inhibition of CYP3A4 activity by oxidized diltiazem metabolites. Journal of Pharmacology and Experimental Therapeutics, 282 (1), 294-300. 

Brain delivery of steroid hormones is also of interest to medicinal chemists. Again, most data available on CDSs of steroids pertain to rates of oxidation of the dihydropyridine carrier, to blood and brain concentrations, and to pharmacological activities. The latter can then be taken as proof of efficient cerebral hydrolysis of the pyridinium metabolite. Thus, the dihydrotrigonelline carrier allowed good brain delivery of estradiol and some other estrogens [181][182],... 

Phenothiazines The phenothiazines (PTZs) undergo extensive metabolism. Metabolic routes include S-oxidation, aromatic hydroxylation, N-dealkylation, N-oxidation, and a combination of these processes. Chlorpromazine, for example, possesses 168 possible metabolites, a large proportion of which are pharmacologically active compounds. The development of an HPLC assay capable of resolving a large number of these metabolites is virtually impossible and assays that permit the simultaneous determination of the parent compound and a selected number of active metabolites must suffice. The PTZ group of compounds includes chlorpromazine, thioridazine, fluphenazine, and perphenazine. 

Ponchaut, S., van Hoof, F. and Veitch, K. (1992) In vitro effects of valproate and valproate metabolites on mitochondrial oxidations. Relevance of CoA sequestration to the observed inhibitions. Biochemical Pharmacology, 43 (11), 2435-2442. 

Gamdner, I., Zahid, N., MacCrimmon, D. and Uetrecht, J.P. (1998) A comparison of the oxidation of clozapine and olanzapine to reactive metabolites and the toxicity these metabolites to human leukocytes. Molecular Pharmacology, 53, 991-998. 

Clonidine is well absorbed after oral administration. Peak plasma levels occur between 2 and 4 hours after drug administration and correlate well with pharmacological activity. The plasma half-life in patients with normal renal function is 12 hours. Urinary excretion of clonidine and its metabolites accounts for almost 90% of the administered dose, and fecal excretion accounts for the rest. Approximately 50% of an administered dose is excreted unchanged the remainder is oxidatively metabolized in the liver. 

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