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A Prox

Publications and source records attributed to A Prox.

At least 19 recordsLinked to original sources
PubMed1999

Disposition and chemical stability of telmisartan 1-O-acylglucuronide.

Telmisartan 1-O-acylglucuronide, the principal metabolite of telmisartan in humans, was characterized in terms of chemical stability and the structure of its isomerization products was elucidated. In addition, pharmacokinetics of telmisartan 1-O-acylglucuronide were assessed in rats after i.v. dosing. Similar to other acylglucuronides, telmisartan 1-O-acylglucuronide and diclofenac 1-O-acylglucuronide, which was used for comparison, showed the formation of different isomeric acylglucuronides on incubation in aqueous buffer. The isomeric acylglucuronides of telmisartan consisted of the 2-O-, 3-O-, and 4-O-acylglucuronides (alpha,beta-anomers). First order degradation half-lives of 26 and 0. 5 h were observed on incubation in buffer of pH 7.4 for the 1-O-acylglucuronides of telmisartan and diclofenac, respectively. This indicated that the 1-O-acylglucuronide of telmisartan was among the most stable acylglucuronides reported to date. The high stability of telmisartan 1-O-acylglucuronide was confirmed by in vitro experiments that indicated only very low covalent binding of telmisartan acylglucuronide to human serum albumin but a considerable amount of covalently bound radioactivity with the acylglucuronide of diclofenac. After i.v. dosing to rats, telmisartan 1-O-acylglucuronide was rapidly cleared from plasma with a clearance of 180 ml/min/kg, compared with 15.6 ml/min/kg for the parent compound. Because telmisartan 1-O-acylglucuronide exhibited a comparably high chemical stability together with a high clearance that resulted in low systemic exposure, the amount of covalent binding to proteins should be negligible compared with other frequently used drugs, such as furosemide, ibuprofen, or salicylic acid.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Meloxicam: metabolic profile and biotransformation products in the rat.

1. The metabolic fate of 14C-labelled meloxicam was investigated in the urine and bile of rat following oral and intraduodenal administration. Structural elucidation of metabolites was performed by nuclear magnetic resonance, mass spectrometry (electron impact and fast atom bombardment). 2. A mean total of 76.3% 14C-radioactivity was recovered in urine over 96 h, with the remainder in the faeces. The metabolic pattern in the excreta was independent of dose (1 versus 10 mg/kg) and collection period (0-8 versus 24-48 h). In bile one of the main metabolites was absent. 3. Meloxicam underwent extensive metabolism with only small amounts of unchanged drug recovered in the urine (< 0.5%) or bile (4.5%). Principal routes of biotransformation were: oxidation of the 5-methyl group of the N-heteroaryl-carbamoyl side chain to yield the 5'-hydroxymethyl derivative (33% of metabolites in urine, 22% in bile) and the 5'-carboxy derivative (16% in urine, 49% in bile). Oxidative cleavage of the benzothiazine-ring yielded an oxamic acid metabolite in urine (23.5%), which was not present in bile. 4. The introduction of a methyl-group into the N-heteroaryl-carbamoyl side chain increased lipophilicity and facilitated metabolic excretion compared with structurally related compounds.

Animals↗
PubMed1990

Quaternary N-glucuronides of 10-hydroxylated amitriptyline metabolites in human urine.

1. Conjugated metabolites were isolated from the urine of patients receiving amitriptyline treatment using a combination of solid-phase extraction, h.p.l.c. and t.l.c. 2. By n.m.r. and mass spectrometry, N-glucuronides of E- and Z-10-hydroxyamitriptyline and of trans-10,11-dihydroxyamitriptyline were identified in addition to the previously described O-glucuronides of E- and Z-10-hydroxyamitriptyline and -nortriptyline and amitriptyline-N-glucuronide. 3. The quaternary ammonium glucuronides proved to be resistant to acid hydrolysis, but could be cleaved enzymatically. 4. In urine samples from three patients, 35-60% of conjugated 10-hydroxyamitriptyline was found in the form of N-glucuronides. 5. A volunteer given an i.v. infusion of amitriptyline-N-glucuronide excreted E- and Z-10-hydroxyamitriptyline-N-glucuronide; following ingestion of E-10-hydroxyamitriptyline its N-glucuronide could be measured in urine.

Adult↗
PubMed1990

Epimerization of erythromycin derivatives.

Dirithromycin (3) isomerizes upon dissolution in different solvents. From X-ray analysis of V-T 108, an analogue of dirithromycin, and comparative 1H and 13C NMR, and MS data, the isomer of dirithromycin was confirmed to be the C-16-(S)-epimer. The ratio of the two epimers at equilibrium conditions was approximately 8:2 (R/S) in methanol at room temperature.

Anti-Bacterial Agents↗
PubMed1987

In vivo screening of glutathione related detoxification products in the early state of drug development.

Glutathione (GSH) adducts and consecutive degradation products thereof are indications of reactive intermediates during drug metabolism. As demonstrated with the analgesic SX-PP 16 (4-amino-3,5-dibromacetanilide), however, interactions of a drug with GSH can be detected by labelling the GSH-stores with labelled cysteine, and consecutive administration of the unlabelled drug even at therapeutic doses. The GSH-adducts are sensitively and specifically traced by HPLC, applying column-switching and a combination of diode-array- and radioactivity detection. This approach seems to be much more sensitive than a classical GSH-depletion study. The structure of the main metabolite of SX-PP 16 (46% of urinary excretion) was elucidated as 3-bromo-4-amino-5-mercapturyl-acetanilid.

Acetanilides↗
PubMed1985

[Metabolism of beclobrate in rat and man].

The major pathway of biotransformation of beclobrate [(2-[4-[(4-chlorophenyl)methyl]phenoxy]-2-methylbutyric acid ethyl ester] is the ester cleavage to beclobrinic acid (M1), which is eliminated as glucuronide. Subsequent metabolic attack is occurring via oxidation of the methylene bridge to the carbinol (M2) as well as to the benzophenone (M3). The p-chloro substituted phenyl ring is oxidated via a postulated arene oxide to the 2'- and 3'-phenol metabolites (M5 and M6) and to the trans-2',3'-dihydrodiol (M4). Except M4, all metabolites are eliminated exclusively as glucuronides.

Animals↗
PubMed1981

[AR-L 115 BS, comparison of human metabolite pattern and biotransformation with other species].

Following oral administration of 14C labelled 2-[(2-methoxy-4-methylsulfinyl)phenyl]-1H-imidazo[4,5-b]pyridine (AR-L 115 BS) to the rat, rabbit, dog, rhesus monkey, baboon and man the metabolic pattern in plasma and urine was compared and human urinary metabolites were isolated. None of the animal species investigated shows a metabolic pattern identical to that of man. The plasma of rat, dog and rabbit shows wide variation of metabolites with high amounts of two unpolar metabolites of AR-L 115 BS (sulfoxide), namely M0/2 identical with AR-L 114 BS (sulfone with regard to AR-L 115 BS) and M0/1 identical with AR-L 113 BS (sulfide). In comparison to man the urines of the animals show higher amounts of the sulfone (AR-L 114 BS) and the sulfide (AR-L 113 BS). A main pathway of the metabolism of the pyrido-imidazole of the AR-L 115 BS-type is the oxidative pyridine-ring cleavage leading to N-acetylated 5-aminoimidazoles. Further metabolites are characterised by a hydroxyl group in the 6-position of the pyrido-imidazole moiety. Besides the oxidation of tthe sulfoxide function to the sulfone we could also observe the thioether (sulfide) not only of the parent compound itself but also of some of the metabolites in the series of the AR-L 115 BS-biotransformation. The identification of the human urinary metabolites, was carried out by means of TLC, HPLC, UV-, MS- and NMR-spectroscopy.

Administration, Oral↗
PubMed1980

The metabolism of 8-methoxypsoralen in man.

8-Methoxypsoralen is metabolized rapidly and completely in man. Most of the metabolites presently known have their origin in a metabolic attack on the furan moiety yielding an aryl-diol and aryl-acetic-acid and are excreted as conjugates.

Biotransformation↗
PubMed1978

[Studies on the biotransformation of fominoben-HCl in man (author's transl)].

The biotransformation of 3'-chloro-2'-(N-methyl-N-[(morpholino-carbonyl)methyl]aminomethyl)benzanilide hydrochloride (fominoben-HCl, PB 89 Cl, Noleptan) was investigated in man. The most substantial metabolites were quantified. The metabolite patterns of fominoben in urine and plasma are compared. Fominoben, is rapidly and extensively metabolized to many metabolites. At the time of the maximum plasma level. 2 h after an oral dose of 160 mg of 14C-PB 89 Cl, only 1.5% of the plasma radioactivity can be measured as the unchanged initial compound. No parent compound can be found in the urine, only in the stool some traces of fominoben can be detected. The biotransformation can be characterized by four main pathways: 1. cleavage reactions, 2. hydroxylations, 3. cyclisations, 4. conjugations. The reactions 1--3 proceed as well simultaneously as successively.

Adult↗
PubMed1976

[Pharmacokinetics and metabolism of trazodone in man (author's transl)].

After intravenous, intramuscular and oral administration of 25 mg 14C-labelled 2-(3-[4-(m-chlorophenyl)-1-piperazinyl]-propyl)-s-triazolo[4,3-a]pyridin-3-(2H)-one-hydrochloride (trazodone), plasma levels, elimination and metabolite pattern in plasma and urine were investigated. The plasma levels after all routes of administration are almost identical. The absorption of the compound is fast and complete. The elimination of radioactivity occurs in a biphasic manner with a half-life of 1 h for the earlier and 13 h for the second phase, no matter what application route had been chosen. The comparison of the plasma levels of fasted and non-fasted subjects shows a shift of the plasma maximum from 1.5 to 2.5 h following administration and a decrease in the maximum level of 30%. The radioactivity is excreted predominantly by renal processes (70-75% within 72 h). The main product in plasma is unchanged trazodone, whereas in urine it is found only in minute amounts. The radioactivity in urine is represented by conjugates that had formed after hydroxylation on the chlorophenyl residue (20%), by a dihydrodiol-metabolite of trazodone (15%) and by a carboxylic acid originating from oxidative cleavage of the parent compound (35%).

Administration, Oral↗
PubMed1975

[Pharmacokinetics and metabolism of the antiinflammatory agents S-H 766 in man].

Blood and plasma levels as well as urinary and fecal excretion were measured in humans after oral administration of radioactively labelled 4-[j-(2'-fluorobiphenylyl)]-4-hydroxycrotonic acid (S-H 766 MO). The radioactivity in the plasma reaches maximum values of about 10 mug eq./ml 1 to 2 h after application with either form. After repeated administration good agreement is found between the plasma levels measured and those simulated according to the pharmacokinetic parameters obtained after single application. The S-H 766 metabolites were investigated in blood and urine. The substance was found to undergo considerable metabolism, only approximately 2% being excreted in the urine unchanged. The conjugates, which constitute over 60% of the radioactivity of the urine, consist mainly of glucuronides and sulfates. The structure of the aglycones shows that the metabolism occurs along two pathways, by beta-oxidation of the aliphatic side chain into aryl acetic acids and by hydroxylation of the aromatic nucleus to phenolic compounds. It must be assumed that these biotransformations take place both simultaneously and successively.

Adolescent↗