Inactive oxidative metabolit

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],... 

Disposition in the Body. Absorbed after oral administration, but there is thought to be considerable first-pass metabolism rapidly absorbed after intramuscular or subcutaneous injection. The major metabolic reaction is conjugation to form nalbuphine glucuronide (inactive) oxidation to 6-oxonalbuphine occurs, and the desalkyl derivative, 7,8-dihydro-14-hydroxynormor-phine, has also been identified as a metabolite. Unchanged nalbuphine, its conjugates, and the two metabolites have been detected in the urine. 

Meclofenamic acid is an anthranilic acid derivative that is typically administered orally to horses. The pharmacokinetics of this NSAID in horses has been well defined. For example, the plasma half-life in horses has been determined in several studies and varies between 0.7 and 1.4 h (Johansson et al 1991, Snow et al 1981). Absorption is variable after oral dosing with estimates of bioavailability ranging from 60 to 90% and peak plasma concentrations occurring 1-3 h after administration (Johansson et al 1991). The effect of ingesta on the absorption of meclofenamic acid from the gastrointestinal tract has not been determined definitively. In one study, the absorption rate of the NSAID was the same in ponies whether they were fasted or fed (Snow et al 1981). However, another study found that absorption of meclofenamic acid was delayed in horses allowed free access to hay (May Lees 1999). In horses, the liver metabolizes meclofenamic acid primarily by oxidation to an active hydroxymethyl metabolite, which may be further oxidized to an inactive carboxyl metabolite (Plumb 1999). 

Tolbutamide is absorbed rapidly in rc.sponsivc diabetic patients. The blood sugar level reaches a minimum after. I 10 8 hours. It is oxidized rapidly in vivo to I-bulyl-3-(/7-carboxyphenyOsulfonylurca. which is inactive. The metabolite is freely. soluble at urinary pH if the urine is strongly acidified, however, as in the use of sulfosalicylie acid as a protein precipitant, a white precipitate of the l rce acid may be formed. 

Figure 15.6. Metabolism of bufuralol (15) produces oxidative, active metabolites (16), (17)that lead to a final inactive acid metabolite (18).Starting from a designed (hypothetical)inactive metabolite (20), a series of inactive metabolite-based soft compounds (19) were designed.

Dezocine has a half-life of 2.6 to 2.8 hours in healthy patients and 4.2 hours in patients with liver cirrhosis. The onset of action of dezocine is faster (30 minutes) than equivalent analgesic doses of morphine, and its duration of action is longer (4-6 hours). Dezocine is extensively metabolized by glucuronidation of the phenolic hydroxyl group and by N-oxidation. Metabolites are inactive and excreted mostly via the renal tract. 

VA is primarily metabolized by oxidation in the liver, producing active and inactive glucuronide metabolites. 

Disulfiram inhibits the initial metabolism (A-demethylation and oxidation) of both chlordiazepoxide and diazepam by the liver so that an alternative but slower metabolic pathway is used. This results in the accumulation of these benzodiazepines in the body. In contrast, the metabolism (glucuronidation) of oxazepam and lorazepam is minimally affected by disulfiram so that their clearance from the body remains largely unaffected. The possible interaction between disulfiram and temazepam is not understood, as temazepam is also mainly eliminated in the urine as the inactive glucuronide metabolite, and so its metabolism would not be expected to be affected by disulfiram. 

Metabolites of retinoids are largely excreted in the feces and urine. The feces primarily contain biliary excretion products, although some unabsorbed retinoid of dietary origin is also present. The urine contains mainly chain-shortened metabolic products. Because very little, if any, retinoid is excreted as such, the products that appear in the excreta are almost entirely biologically inactive, oxidized, or conjugated compounds. 

DDT undergoes several in vivo oxidative dehydrohalogenation steps and direct oxidation toward an inactive acidic metabolite (30) [115]. This inactive acid metabolite is of low toxicity, can be excreted as a water-soluble species, and is. 

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. 

Conversion of epoxides (arene oxides) into phenols is spontaneous. The conversion of epoxides into dihydrodiols is catalyzed by EH (EC 4.2.1.63). Hydroxyl containing PAHs can act as substrates for conjugases (C) (UDP glucuronsyl transferase (EC 2.4.1.17) and phenol sulphotransferase (EC 2.8.2.1)). This pathway usually leads to inactive excretable products. Epoxides are scavenged by GSH and the reaction is catalyzed by GSHt (EC 2.5.1.18). When GSH is depleted and/or the other pathways are saturated, epoxides of dihydrodiols (particularly 7,8-diol-9,10-epoxides in the case of BP) and phenol metabolites react with cellular macromolecules such as DNA, RNA, and protein. If repair mechanisms are exceeded the detrimental effects of PAH may result. 

Zopiclone is widely used as a sedative-hypnotic. It is metabolized to an inactive N-desmethylated derivative and an active N-oxide compound, both of which contain chiral centres. S-Zopiclone has a 50-fold higher affinity for the benzodiazepine receptor site than the R-enantiomer. This could be therapeutically important, particularly if the formation and the urinary excretion of the active metabolite benefits the S-isomer, which appears to be the case. As the half-life of the R-enantiomer is longer than that of the S-form, it would seem advantageous to use the R-isomer in order to avoid the possibility of daytime sedation and hangover effects which commonly occur with long-acting benzodiazepine receptor agonists. 

Although demethylation, which occurs in the liver, is normally considered to be a catabolic process, it may result in conversion of an inactive form of a drug to the active form. Thus 6-(methylthio)purine (XXXIX) is demethylated by the rat to 6-mercaptopurine [205]. This demethylation occurs in the liver micro-somes and is an oxidative process which converts the methyl group to formaldehyde [204, 207]. The 1-methyl derivative of 4-aminopyrazolo[3,4-d] pyrimidine (XLI) is demethylated slowly, but 6-mercapto-9-methylpurine (XLII) not at all [208]. The A -demethylation of puromycin (XLlIl) [209, 210], its aminonucleoside (XLIV) [211], and a number of related compounds, including V-methyladenine and V,V-dimethyladenine, occurs in the liver microsomes of rodents [212]. In the guinea-pig the rate-limiting step in the metabolism of the aminonucleoside appears to be the demethylation of the monomethyl compound, which is the major urinary metabolite [213]. The relationship of lipid solubility to microsomal metabolism [214], and the induction of these demethylases in rats by pre-treatment with various drugs have been studied [215]. 

The amide type local anesthetic lidocaine is broken down primarily in the liver by oxidative N-dealkylation. This step can occur only to a restricted extent in prilocaine and articaine because both carry a substituent on the C-atom adjacent to the nitrogen group. Articaine possesses a carboxymethyl group on its thiophen ring. At this position, ester cleavage can occur, resulting in the formation of a polar -COO group, loss of the amphiphilic character, and conversion to an inactive metabolite. 

Metabolism - Linezolid is primarily metabolized by oxidation of the morpholine ring, which results in 2 inactive metabolites. Linezolid is not detectably metabolized by human cytochrome P-450 and it does not inhibit the activities of clinically significant human CYP isoforms. 

Combining different IMNs with common receptor sites enhances efficacy, low dosages avoid dose-dependent hematological adverse effects because of the different receptor sites for side effects and finally, cyclosporin (CyS) may block oxidation of MTX to its relatively inactive metabolite, 7-OH-MTX, thereby potentiating MTX efficacy. 

Acyclovir absorption is variable and incomplete following oral administration. It is about 20% bound to plasma protein and is widely distributed throughout body tissues. Significant amounts may be found in am-niotic fluid, placenta, and breast mUk. Acyclovir is both filtered at the glomeruU and actively secreted. Most of the dose is excreted in the urine as unchanged drug a small portion is excreted as an oxidized inactive metabolite. The plasma half-Ufe of acyclovir is 3 to 4 hours in patients with normal kidney function and up to 20 hours in patients with renal impairment. 

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