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. 

Kielbasa W, Fung HL Pharmacokinetics of a model organic nitrite inhalant and its alcohol metabolite in rats. Drug Metab Dispos 28 386-391, 2000... 

In conclusion, the oxamic acid derivative is produced by two distinct metabolic pathways, namely by oxidative and hydrolytic dechlorinations. In contrast, the primary alcohol metabolite 11.41 can be produced only by hydrolytic dechlorination and is, thus, an unambiguous marker of this pathway. The alcohol 11.41 is a known urinary metabolite of chloramphenicol in humans. 

Most of the human experience with disulfiram has come from its use as an avoidance therapy for alcoholism. Metabolites of disulfiram inhibit aldehyde dehydrogenase, resulting in elevated levels of acetaldehyde after ethanol ingestion. Side effects include flushing of the face, tachycardia, severe headache, apprehension, hyperpnea, hypotension, dizziness, nausea, vomiting, and fainting. Severe reactions may include convulsions, myocardial infarction, and marked respiratory depression. ... 

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. 

Pentobarbital is biotransformed by oxidation of the penultimate carbon of the methyl butyl side-chain to produce a mixture of alcohols, and by iV -hydroxylation. The alcoholic metabolites of pentobarbital are pharmacologically inactive. Approximately 86% of a radioactive dose is excreted in the urine in 6 days, about 1% as unchanged drug and up to 73% as the L- and D-diastereoisomers of 3 -hydroxypentobarbital in a 5.4 1 ratio, and up to 15% as JV-hydroxypentobarbital.9 None of these metabolites is eliminated as a conjugate. 

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. 

A rhesus monkey study is also included (66) which species shows the trans-alcohol metabolite excreted as well. Urinary excretion consists of unchanged pentazocine and metabolites plus phenolic glucu-ronides of each. Fecal excretion consists of less than 1% administered dose (86). 

Oral bioavailability of mibefradil is dose dependent and ranges from 37% to over 90% with doses of 10 mg or 160 mg, respectively. The plasma half-life is 17 to 25 hours after multiple doses, and it is more than 99% protein bound (15). The metabolism of mibefradil is mediated by two pathways esterase-catalyzed hydrolysis of the ester side chain to yield an alcohol metabolite and CYP3A4-catalyzed oxidation. After chronic dosing, the oxidative pathway becomes less important and the plasma level of the alcohol metabolite of mibefradil increases. In animal models, the pharmacological effect of the alcohol metabolite is about 10% compared to that of the parent compound. After metabolic inactivation, mibefradil is excreted into the bile (75%) and urine (25%), with less than 3% excreted unchanged in the urine. 

Acid-labile Oxygenated Metabolite. The 2° alcohol metabolite (Figure 1, R2=0H) was first Isolated in moderate yield from the ethyl acetate phase after solvent partitioning ( 6). Because yields of the free 2° alcohol in this phase sometimes were observed to Increase when the partitioning steps were delayed, decomposition of an unstable polar metabolite may release this oxygenated material. 

Israel, Y., Orrego, H., Nlemelae, O. Immune responses to alcohol metabolites pathogenic and diagnostic implications. Semin. Liver Dis. 

Alkyl or aliphatic carbon centers are subject to mixed-function oxidation. Metabolic oxidation at the terminal methyl group often is referred to as to oxidation, and oxidation of the penultimate carbon atom (i.e., next-to-the-last carbon) is called to - I oxidation." " The initial alcohol metabolites formed from these enzymatic to and to - I oxidations are susceptible to further oxidation to yield aldehyde, ketones, or ca xylic acids. Alternatively, the alcohol metabolites may undergo glucuronide conjugation. 

Various studies regarding the biotransformation of xenobiotic ketones have established that ketone reduction is an important metabolic pathway in mammalian tissue. Because carbonyl compounds are lipophilic and may be retained in tissues, their reduction to the hydrophilic alcohols and subsequent conjugation are critical to their elimination. Although ketone reductases may be closely related to the alcohol dehydrogenases, they have distinctly different properties and use NADPH as the cofactor. The metabolism of xenobiotic ketones to free alcohols or conjugated alcohols has been demonstrated for aromatic, aliphatic, alicyclic, and unsaturated ketones (e.g., naltrexone, naloxone, hydromorphone, and daunorubicin). The carbonyl reductases are distinguished by the stereospecificity of their alcohol metabolites. 

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