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.

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).

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.

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.

Glucuronides of hydroxylated metabolites of amitriptyline and nortriptyline isolated from rat bile.

Polar conjugates were isolated from the bile of rats given amitriptyline (AT, unlabeled or labeled with 14C), nortriptyline (NT), or 10-hydroxy (10-OH) derivatives of the drugs. The procedure involved extraction on a column of polystyrene resin, elution with methanol, and separation by preparative TLC followed by reversed phase HPLC. Individual metabolites were characterized by NMR spectroscopy and fast atom bombardment mass spectrometry and by enzymatic or acid deconjugation with subsequent identification of aglycones and glucuronic acid.

Amitriptyline metabolites in human urine. Identification of phenols, dihydrodiols, glycols, and ketones.

From the urine patients being treated with amitriptyline, drug metabolites were extracted by adsorption to polystyrene. Nonconjugated compounds and aglycones liberated by enzymic hydrolysis were purified separately by repeated TLC and characterized by physicochemical and chemical methods. Besides the known E- and Z-10-hydroxy derivatives of amitriptyline (AT), nortriptyline (NT), and their primary amine analogue, two isomeric 10,11-dihydroxy compounds could be identified in each series.

Phenolic metabolites of amitriptyline and nortriptyline in rat bile.

Anesthetized bile fistula rats received amitriptyline (AT), its N-oxide (AT-NO), or nortriptyline (NT) at doses of 72 mumol/kg ip, and bile was collected for 6-9 hr. Isolation of metabolites was achieved by enzymic deconjugation and repeated TLC of extracted aglycones. Purified compounds were characterized by UV, NMR, and mass spectrometry, by color reactions, and by chemical interconversions.

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.

Phenolic metabolites of chlorprothixene in man and dog.

From urine and feces of dogs and urine of patients given chlorprothixene (CPT) per os, metabolites were extracted without or with enzymatic deconjugation and separated by repeated TLC. Purified compounds were characterized by UV, NMR, and mass spectrometry, by color reactions, and by chemical interconversions. Both species excreted 6- and 7-hydroxy-CPT besides the sulfoxide and demethylated analogues.

[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).

[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).

The use of stable isotopes to prove the saturable first-pass effect of methoxsalen.

Methoxsalen, administered orally shows a strong, albeit saturable first-pass effect, as demonstrated by classical dose linearity testing and by a new method, using stable isotopes and gas chromatographic mass spectrometric analysis. The therapeutic consequences of the first-pass effect are discussed.

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.

Formation of sulfone metabolites from chlorpromazine and perazine in man.

Didesmethylchlorpromazine sulfone [gamma-(2-chlorophenothiazinyl-10)-propylamine sulfone] has been isolated from the urine of a patient under continuous chlorpromazine therapy and identified by mass spectrometry. The same compound was present in organs of rats after injection of the corresponding sulfide. The Cl-free analogue, gamma-(phenothiazinyl-10)-propylamine sulfone, was excreted by patients receiving perazine and by a volunteer after ingestion of the primary amine sulfoxide.

[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.

[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.

[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.