Pharmacokinetics and metabolism of nateglinide in humans.

The pharmacokinetics and metabolism of nateglinide were studied in six healthy male subjects receiving a single oral (120 mg) and intravenous (60 mg) dose of [14C]nateglinide in randomized order. Serial blood and complete urine and feces were collected for 120 h post dose. Nateglinide was rapidly (approximately 90%) absorbed, with peak blood and plasma concentrations at approximately 1 h post dose. The maximal plasma concentrations of radioactivity (6360 ngEq/ml) and nateglinide (5690 ng/ml) were comparable, and plasma radioactivity concentrations were about twice those of blood at all times. Oral bioavailability was 72%, indicating only a modest first-pass effect. After either dose, plasma nateglinide concentrations declined rapidly with elimination half-lives of 1.5 to 1.7 h and plasma clearance of 7.4 l/h. Plasma radioactivity was eliminated more slowly with half-lives of 52 and 35 h in plasma and blood, respectively, after the oral dose. The contribution of this more slowly eliminated component to the AUC(0-infinity) was minor. Nateglinide was extensively metabolized, with excretion predominantly (84-87%) in urine. Only approximately 16% of the dose was excreted unchanged in urine after either dosing route. The major metabolites were the result of oxidative modifications of the isopropyl group. Three of these were monohydroxylated, two of which appeared to be diastereoisomers. Additionally, one metabolite with an unsaturation in the isopropyl group and two diol-containing isomers were identified. Glucuronic acid conjugates resulting from direct glucuronidation of the carboxylic acid were also present. The major metabolite in plasma and urine was the result of hydroxylation of the methine carbon of the isopropyl group.

Pharmacokinetics and metabolism of alpha-[(dimethylamino)methyl]-2- (3-ethyl-5-methyl-4-isoxazolyl)-1H-indole-3-methanol, a hypoglycemic agent, in man.

1. The pharmacokinetics and metabolism of alpha-[(dimethylamino)methyl]-2-(3-ethyl-5-methyl-4-isoxazolyl) -1H-[3-14C]indole-3-methanol, a new hypoglycemic agent, have been studied in 15 healthy male volunteers who received an oral dose of 50 or 200 mg. 2. The drug was rapidly and almost completely absorbed intact from the gastrointestinal tract. 3. Compared with the 50 mg dose, the 200 mg dose yielded less than proportionally higher blood concentrations of radioactivity and unchanged drug. This phenomenon has been observed previously in the rat and was probably due to an increase in drug distribution volume with increasing dose, since the metabolism and excretion patterns of the drug appeared to be dose-independent. 4. The drug was partially metabolized prior to excretion. Approximately 40% of the dose was recovered intact, almost exclusively in urine. The major metabolic pathway of the drug was by conjugation with glucuronic acid, while oxidation of the indole ring gave rise to a relatively minor metabolite. 5. The recovery of administered radioactivity was virtually complete within the experimental period, with a renal:faecal excretion ratio of ca 80:20. The elimination half-life of unchanged drug was 25-30 h while that of total radioactivity was 33-35 h.

The biotransformation of fluproquazone in man and several animal species.

The biotransformation of 4-(p-fluorophenyl)-1-isopropyl-7-methyl-2(1H)-quinazolinone (fluproquazone) has been investigated in man, mouse, rat, rabbit, and dog. Single oral doses of 3H-fluproquazone were administered to the animals (15 mg/kg). Human volunteers received 100 mg 3H-fluproquazone t.i.d. for 5 days (3.8 mg/kg). Two potential metabolites were synthesized: 4-(p-fluorophenyl)-1,2-dihydro-1-isopropyl-2-oxo-7-quinazolinecarboxylic acid (4) and 4-(p-fluorophenyl)-7-hydroxymethyl-1-isopropyl-2(1H)-quinazolinone (11). The human urinary metabolites of fluproquazone were separated and purified by a combination of extractions and liquid chromatography on reversed-phase columns, and structures were proposed on the basis of identify with known standards, mass spectral data, and retention time comparison. Definitive structures were assigned to five metabolites. Fluproquazone and its metabolites were characterized and quantitated in the blood, urine, and feces of man, mouse, rat, rabbit, and dog by high-pressure liquid chromatography coupled to a radioactivity monitor or by reverse isotope dilution analysis. Significant quantities of fluproquazone were noted in the blood of all species. The major circulating metabolite in blood at or near the peak of radioactivity was 11 in rat, mouse, and dog and 4 in man and rabbit. In all species analyzed, 4 was the major metabolite excreted in the urine and feces. In man the minor metabolites consisted of 11 as a conjugate and several phenolic derivatives also conjugated. The animals were exposed to the same major metabolite as man and each minor metabolite found in man, with the exception of a few very minor ones, was identified in at least one of the animal species. The metabolite pattern did not vary significantly among the 3 human subjects analyzed nor over the 5-day dosing period. Two biotransformation pathways were identified. The major pathway was sequential oxidation with or without conjugation of the 7-methyl group; aromatic hydroxylation and conjugation was a minor pathway.

Biotransformation of mazindol. I. Isolation and identification of some metabolites from rat urine.

Three metabolites of tritium-labeled mazindol were isolated from rat urine by the inverse isotope-dilution technique in which the labeled metabolites were synthesized by a second, smaller group of rats. These metabolites were isolated by Amberlite XAD-2 chromatography and silica gel column and preparative thin-layer chromatography. The major metabolite (II) was shown by mass spectrometry of its trimethylsilyl derivative. NMR spectroscopy, and degradation studies to be 5-(p-chlorophenyl)-2,5-dihydro-5-hydroxy-3H-imidazol(2,1-a)isoindol-3-one. A comparison of its mass spectrum with that of an authentic sample prepared from 1-(p-chlorophenyl)-3-ethoxy-1-methoxy-1H-isoindole and glycine ethyl ester confirmed the assignment. Metabolite III was shown by its mass spectrum, NMR spectrum, degradation, and analogy with metabolite II to be 5-(p-chlorophenyl)-2,5-dihydro-2,5-dihydroxy-3H-imidazo (2,1-a)isoindol-3-one. Only a small amount of metabolite IV was isolated as an artifact, 3-(p-chlorophenyl)-2-glycyl-3-methoxy-1-isoindolinone, as shown by its mass spectrum and degradation to 2-(p-chlorobenzoy)benzoic acid. The metabolite IV is believed to be the corresponding 3-hydroxy compound. Synthesis of IV by base-catalyzed hydrolysis of metabolite II supports the structural assignment. In addition, the facile conversion of synthetic IV into the corresponding 3-methoxy derivative by acidic methanol was also observed.