Carboxylic acid metabolite

In man, the metabolic pathways of mepirizole were distinct from those in experimental animals, since hydroxylation on each of the aromatic rings did not occur in man. Compound (752) was obtained by oxidation of the 3-methyl group to the carboxylic acid (a similar process occurs with 5-methylpyrazole-3-carboxylic acid, an active metabolite of 3,5-dimethylpyrazole). However, the carboxylic acid metabolite of mepirizole had no analgesic activity and did not decrease blood glucose. 

Mihaly et al. [127] examined the pharmacokinetics of primaquine in healthy volunteers who received single oral doses of 15, 30, and 45 mg of the drug, on separate occasions. Each subject received an intravenous tracer dose of 14C-prima-quine (7.5 pCi), simultaneously with 45 mg oral dose. Absorption of primaquine was virtually complete with a mean absorption bioavailability of 0.96. Elimination half-life, oral clearance, and apparent volume of distribution for both primaquine and the carboxylic acid metabolite were unaffected by either dose size or route of administration. 

W. G. Taylor, R. W. Spooner, Identification and Gas Chromatographic Determination of Some Carboxylic Acid Metabolites of V,V-Diethyl-m-Toluamide in Rat Urine , J. Ag-ric. Food Chem. 1990, 38, 1422-1427. 

A patent from Ortho disclosed naphthoylvalerohydroxamic acids which inhibit 5-HETE release from RBL-1 cells (0.1 /rM) and also showed oral activity in RAA [292], The most potent compound (51 % at 50 mg/kg) was the A-isopropyl analogue (115). Although only the hydroxamic acids inhibited 5-LO activity, simple acids and esters showed comparable RAA activity, suggesting that the hydroxamic acids yielded an anti-inflammatory carboxylic acid metabolite. 

MefaboZ/s/T - Tolterodine undergoes extensive and variable first-pass hepatic metabolism following oral dosing. The primary metabolic route involves the oxidation of the 5-methyl group mediated by the cytochrome P450 2D6 leading to the formation of an active 5-hydroxymethyl metabolite. Further metabolism leads to formation of the 5-carboxylic acid and N-dealkylated 5-carboxylic acid metabolites, which account for approximately 51% and approximately 29% of the metabolites recovered in the urine, respectively. 

Remifentanil, recently approved for use in the United States and Europe, is the first truly ultra-shortacting opioid. Remifentanil s uifique ester linkage allows it to be rapidly degraded to an inactive carboxylic acid metabolite by nonspecific esterases found in tissue and red blood cells. Since it is not a good substrate for plasma pseudocholinesterase, deficiency of the enzyme does not influence its duration of action. Also, hepatic and renal insufficiencies do not influence remifentanil s pharmacokinetics, so it is useful when liver or kidney failure is a factor. Because of its rapid clearance following infusion, remifentanil has gained popularity as an agent for maintenance of anesthesia when an IV technique is practical. 

Ribavirin is reversibly phosphorylated by all nucleated cells. It is also metabolized in the liver to a triazole carboxylic acid metabolite that is eliminated in the urine along with the parent compound. The plasma half-life of ribavirin is 9.5 hours when it is administered by aerosol (2.5 hours/day for 3 days), whereas its half-life is around 12.5 days at steady state. The drug accumulates in erythrocytes, with a half-life of 40 days. 

In humans, only the jV-desethyl metabolite is detected in whole blood, although trace amounts of the other two metabolites are found in urine. All three of the above exhibit binding to carbonic anhydrase and prolonged half-lives in whole blood. In rats, a carboxylic acid metabolite formed by oxidation of the O-desmethyl analog is the predominant urinary metabolite. Small amounts of this compound are also found in human urine. 

Thiopentone is metabolised in the liver to hydroxythiopentone and the carboxylic acid metabolite, both of which are more water-soluble and almost devoid of CNS activity. The low clearance of thiopentone (3.4 mL-kg-l-min-1) contributes to a relatively long elimination half-life... 

Esmolol is an ultra-short-acting relatively 31-selective 3-adrenoceptor antagonist with an elimination half-life of about 9 min. After intravenous administration it is rapidly hydrolysed by non-specific esterases in the blood and tissues to a carboxylic acid metabolite. Following an intravenous infusion its haemodynamic effects are short lasting and disappear within 20-30 min. The main indication in the perioperative period is to treat tachycardia. 

Kelley, I., Freeman, J. P., Evans, F. E. Cerniglia,C. E. (1991). Identification of a carboxylic acid metabolite from the catabolism of fluoranthene by a Mycobacterium sp. Applied and Environmental Microbiology, 57, 636—41. 

Permethrin Urinary carboxylic acid metabolites Exposure pathways risk assessment external dose to toxic effect in animals Biomarker results can be put into risk context by using existing risk assessment... 

A metabolite with +16 amu is generally suspected of forming by hydrox-ylation (or by some other reaction involving the addition of oxygen). However, a metabolite with +14 amu is often suspected of forming by methylation (+CH2), not by a combination of the addition of oxygen (+16) and dehydrogenation (—2). NADPH-fortified human liver microsomes cannot catalyze the methylation of dmg candidates (such reactions are catalyzed by cytosolic enzymes in the presence of. S -adenosylmethionine). However, methylation can sometimes occur as an artifact when mass spectrometry is conducted in the presence of methanol (164), and [M + 12] adducts can form from condensation reactions with formaldehyde, which is a microsomal metabolite of methanol (165). A metabolite with +30 amu is indicative of either formation of a carboxylic acid metabolite or a combination of hydroxylation (+16) and methylation (+14). Only the former can be catalyzed by NAPDH-fortified liver microsomes. 

Steams RA, Chakravarty PK, Chen R, et al. Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes. Role of cytochrome P4502C and 3A subfamily members. Drag Metab Dispos 1995 23(2) 207-215. 

Disposition in the Body. Incompletely absorbed after oral administration (about 35%) rapidly hydrolysed to the corresponding carboxylic acid. About 70% of an intravenous dose and 20% of an oral dose is excreted in the 24-hour urine as the carboxylic acid metabolite. 

Following oral administration of 150 mg three times a day to 6 subjects, a peak plasma concentration of 0.9 pg/ml of the carboxylic acid metabolite was reported, declining to 0.06 pg/ml, 10 hours after the last dose (Y. C. Martin and R. G. Wiegand, J.p/iarw. Sci., 1970,59,1313-1318). 

Half-life. Plasma half-life, carboxylic acid metabolite about 0.8 hour. 

Volume of Distribution. Carboxylic acid metabolite, about 0.4 litre/kg. 

Disposition in the Body. Readily absorbed after oral administration. About 50 to 70% of a dose is excreted in the urine as unchanged drug in 24 hours, and up to 15% may be excreted as inactive aldehyde and carboxylic acid metabolites up to 20% of an oral dose may be eliminated in the faeces. 

Markuszewski, M.J., Otsuka, K., Terabe, S., Matsuda, K., Nishioka, T. Analysis of carboxylic acid metabolites from the tricarboxylic acid cycle in Bacillus subtilis cell extract by capillary electrophoresis using an indirect photometric detection method. J. Chromatogr. A 1010, 113-121 (2003)... 

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. 

Ebastine is a second-generation antihistamine with proven efficacy in the treatment of allergic disease (1). It is rapidly absorbed after oral administration, and undergoes extensive first-pass metabolism by CYP3A4 to its active carboxylic acid metabolite, carebastine. 

In 1990, etretinate (Tigason) was replaced by acitretin (Neo-Tigason), an aromatic retinoid, a carboxylic acid metabolite of etretinate (15). It is effective in pustular psoriasis and psoriatic palmoplantar keratoderma and in combination with PUVA or topical therapy (calci-potriol or glucocorticoids) in the treatment of other forms of psoriasis. It has also been used to treat disorders of keratinization (ichthyosis, palmoplantar keratoderma, Darier s disease) and severe cutaneous forms of lichen planus. It prevents new skin carcinomas in patients with xeroderma pigmentosum and those who are immunosuppressed. The main advantage of acitretin is its short half-life of 50 hours, compared with over 80 days for etretinate (16). 

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