Secondary alcohol metabolite

Substituting EPI for DOX Lower formation of ROS or secondary alcohol metabolite Same as those of DOX combination with drugs that stimulate anthracycline conversion to secondary alcohol metabolite or diminish the cardiac defenses against ROS... 

DOX, as EPI seems to form fewer amounts of ROS and secondary alcohol metabolite, (ii) encapsulation of anthracyclines in uncoated or pegylated liposomes that ensure a good drug delivery to the tumor but not to the heart, (iii) conjugation of anthracyclines with chemical moieties that are selectively recognized by the tumor cells, (iv) coadministration of dexrazoxane, an iron chelator that diminishes the disturbances of iron metabolism and free radical formation in the heart, and (v) administration of anthracyclines by slow infusion rather than 5-10 min bolus (Table 1). Pharmacological interventions with antioxidants have also been considered, but the available clinical studies do not attest to an efficacy of this strategy. 

The most significant metabolite of letrozole (3) is its secondary alcohol metabolite (SAM) 23 (Scheme 3.4). Biotransformation of letrozole is the main elimination mechanism, with the glucuronide conjugate of the secondary alcohol metabolite (24) being the prominent species found in urine. However, the total body clearance of letrozole is slow (2.21 L/h). Its elimination half-life is long, at 42 h. Letrozole and its metabolites are excreted mainly via the kidneys. 

Minotti, G. et al. (1995) Secondary alcohol metabolites mediate iron delocalization in cytosolic fractions of myocardial biopsies exposed to anticancer anthracyclines novel linkage between anthracycline metabolism and iron-induced cardiotoxicity, J. Clin. Invest. 95, 1595-605. 

The active secondary alcohol metabolites formed by aldoketoreductase induce a prolonged inhibition of... 

The formation of another metabolite, l-hydroxybut-3-ene-2-one (10.109), postulated to arise by dehydrogenation of the secondary alcoholic group, could be demonstrated only indirectly. l-Hydroxybut-3-ene-2-one is believed to react with glutathione and other endogenous nucleophiles, to be oxidized to 2-oxobut-3-enoic acid (10.110), and to break down to form unidentified products. 

Free and conjugated forms of the major metabolite, secondary alcohol of ethchlorvynol. Active metabolite, desalkylflurazepam. 

Aliphatic hydroxylation. As well as unsaturated aliphatic compounds such as vinyl chloride mentioned above, which are metabolized by epoxidation, saturated aliphatic compounds also undergo oxidation. The initial products will be primary and secondary alcohols. For example, the solvent n-hexane is known to be metabolized to the secondary alcohol hexan-2-ol and then further to hexane-2,5-dione (Fig. 4.9) in occupationally exposed humans. The latter metabolite is believed to be responsible for the neuropathy caused by the solvent. Other toxicologically important examples are the nephrotoxic petrol constituents, 2,2,4- and 2,3,4-trimethylpentane, which are hydroxylated to... 

The metabolism of isopropanol is via oxidation by aldehyde dehydrogenase (ADH) to acetone. In common with other a-substituted (secondary) alcohols, isopropanol is a relatively poor substrate for ADH (WHO, 1990 Light et al., 1992). The primary metabolite, acetone, is eliminated in the expired air and in the urine and also undergoes further oxidation to acetate, formate and, ultimately, CO,. 

Many other microorganisms have been studied in relation to the degradation of envirtmmaiUd hydrocarbon pollutants however the identification of metabolites and elucidation of metabolic pathways has often been the prime concern of these studies, rather than the develqnnent of synthetic tnediods. Methyl-otropic bacteria are noted for their ability to degrade hydrocarbons and in some cases intermediate hy-droxylated products can be recovered. Patel and coworkers have done much of the work in this area and systems capable of converting /i-alkanes to secondary alcohols or ketones have been developed. 

Disposition in the Body. Readily absorbed after oral administration bioavailability about 65%. Haloperidol is localised in the tissues and rapidly taken up by the brain. It is slowly excreted in the urine, about 40% of a dose being eliminated in 5 days with only about 1% of the dose as unchanged drug about 15% of a dose is excreted in the bile. Metabolites which have been identified in urine are 4-fluorobenzoylpropionic acid and 4-fluorophenylaceturic acid (the glycine conjugate of 4-fluoro-phenylacetic acid), both of which are inactive. Haloperidol is also metabolised by reduction of the ketone group to a secondary alcohol. 

Certain biotransformation processes are reversible, and formation of an inactive metabolite that can be converted back to the active drug delays the removal of the drug from the body and probably prolongs the duration of exposure of the target tissues to the drug. The common processes that can contribute to this phenomenon are oxidation/reduction of secondary alcohols/ketones, sulfides/sulfoxides, and tertiary amines/N-oxides, all of which are reversible processes. 

Oxidation of primary [Eq. (1)], secondary [Eq. (2)], or tertiary [Eq. (3)] carbon atoms all occur to give the corresponding alcohols. Further oxidation of a primary alcohol yields the aldehyde, which is usually rapidly converted to the carboxylic acid. The oxidation of secondary alcohols to ketones generally leads to less hydrophilic metabolites and is less common. 

Some biotransformations introduce an asymmetric center into a drug and these often proceed stereospeci-fically. The most common examples are hydroxylation of a secondary carbon and the reduction of ketones to secondary alcohols. Ibuprofen undergoes both co and co-l oxidation of the isobutyl side chain, and formation of the resulting carboxylic acid metabolite introduces a second asymmetric center into the molecule. Both ibuprofen enantiomers have been shown to undergo stereospecific oxidation to give a metabolite with the same configuration at the new asymmetric center. 

Numerous barbiturates and oral hypoglycemic sulfonyl-ureas also have aliphatic side chains that arc su.sceptible to oxidation. Note that the sedative hypnotic amobarbital (Amytal) undergoes extensive to - I oxidation to the corresponding 3 -hydroxylated metabolite.Other barbiturates, such as pentobarbital, thiamylal,and secobarbital," reportedly are metabolized by way of a and to - I oxidation. The ri-propyl side chain attached to the oral hypoglycemic agent chlorpropamide (Diabinc.se) undergoes extensive to -I hydroxylation to yield the secondary alcohol 2 -hydroxy-chlorpropamide as a major urinary metabolite in humans. " ... 

Many oxidative processes (e.g., benzylic, allylic, alicyclic, or aliphatic hydroxylation) generate alcohol or carbinol metabolites as intermediate products. If not conjugated, these alcohol products are further oxidized to aldehydes (if primary alcohols) or to ketones (if secondary alcohols). Aldehyde metabolites resulting from oxidation of primary alcohols or from oxidative deamination of primary aliphatic amines often undergo facile oxidation to generate polar carboxylic acid derivatives." As a general rale, primary alcoholic groups and aldehyde functionalities are quite vulnera-... 

Stypodiol, epistypodiol and stypotriol are secondary diterpene metabolites produced by the tropical brown algae Stypopodium zonaie. These compounds display diverse biological properties, including strong toxic, narcotic, and hyperactive effects upon the reef-dwelling fish. In the laboratory of A. Abad an efficient stereoselective synthesis of stypodiol and its C14 epimer, epistypodiol, was accomplished from (S)-(+)-carvone. The key transformations in the synthesis of these epimeric compounds were an intramolecular Diels-Alder reaction, a sonochemical Barbier reaction and an acid-catalyzed quinol-tertiary alcohol cyclization. 

Cumene is absorbed readily via the inhalation route in man and animals, and is metabolized efficiently, within the body, to water-soluble metabolites that are excreted into the urine. The secondary alcohol 2-phenyl-2-propanol and its conjugates are major metabolites. Neither cumene nor its metabolites are likely to accumulate within the body. Based on controlled studies in humans, the average retention of inhaled cumene in the respiratory tract was 50%. 

---