The pharmacokinetics and the metabolic profile of tomoxiprole, a new analgesic antiinflammatory agent belonging to the class of 3-alkyl-2-aryl-3H-naphth (1,2-d)imidazoles, were studied in the rat. After oral administration (5 mg/kg) to male rats, tomoxiprole was rapidly absorbed, mostly by the gut, and reached maximum plasma levels of about 0.5 microgram/ml in 0.25-2 h. A metabolic first pass reduced the extent of oral bioavailability of the parent compound to about half, while absorption (total 14C data) was estimated to be complete. After intravenous injection (2.5 mg/kg), the plasma kinetics of tomoxiprole in male rats showed a bi-exponential profile, and the terminal elimination half-life was 4.2 h. The apparent volume of distribution was high, suggesting a wide distribution of the drug. Increasing the oral dose by ten times (50 mg/kg), resulted in linear kinetics with a proportional increase of the C max and AUC values and the same value of terminal elimination half-life. In females given a 5 mg/kg dose, the plasma levels of 14C, tomoxiprole and AUC values were somewhat higher than in males. The plasma levels of total 14C after iv or po treatments were higher and more sustained than those of tomoxiprole. The kinetic profile after iv administration was described by a three exponential terms equation and the terminal elimination half-life was 38.7 h. Upon iv administration, total 14C was rapidly distributed in highly vascularized tissues while in others, like the bone, fat, gonads, pancreas and skin the equilibrium with the central compartment was attained later. Target organs were the adrenals, liver, lungs, pancreas, thyroid, stomach and above all the fat tissue. Elimination from tissues was almost complete 48 h after the treatment. 14C was eliminated mainly in the feces (80% of dose) as metabolites. In the bile, five polar metabolites were detected; one of them, desmethyl tomoxiprole glucuronide, accounting alone for more than 80% of the total biliary radioactivity; was purified and its structure assigned.

Analgesics↗

PubMedDate not supplied

Metabolism of deflazacort in the rat, dog and man.

The metabolism of [2'-14C]deflazacort, (11 beta, 16 beta)-21-(acetoxyl)-11-hydroxy-2'-methyl-5'H-pregna-1, 4-dieno[17,16-d]oxazole-3,20-dione, orally given to rats, dogs, and humans, has been studied. From the urine of the three species and from rat bile and liver preparations, five main metabolites I-V have been isolated and their structures investigated by physicochemical analysis: 1,(5 beta,11 beta,16 beta)-11,21-dihydroxy-2'-methyl-5'H-pregn-1-eno[17,16-d]oxazole-3,20-dione; II, (11 beta,16 beta)-11,21-dihydroxy-2'-methyl-5'H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione; III, (6 beta,11 beta,16 beta)-6,11,21-trihydroxy-2'-methyl-5'H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione; IV, (3 epsilon,11 beta,16 beta)-3,11,21-trihydroxy-2'-methyl-5'H-pregn-5-eno[17,16-d]oxazol-20-one. Metabolites II and III are quantitatively the most important in the urine of the rat, dog, and man; metabolite V, whose structure is uncertain, has been found in human and rat urine. In the formation of metabolites I-V the fused 2-methyloxazoline ring is unmetabolized, whereas the steroid moiety follows the general metabolic pathways reported for other related corticosteroids.

Animals↗

PubMedDate not supplied

Metabolic fate of premazepam, a new anti-anxiety drug, in the rat and the dog.

A study of the disposition and metabolism of premazepam, 3,7-dihydro-5-phenyl-6,7-dimethyl-pyrrole[3,4-e][1,4]diazepin-2-(1 H) -one, a new anti-anxiety agent, was carried out in rats and dogs given the 14C-labeled compound iv and po. In both species, after oral administration, both total radioactivity and the unchanged drug are rapidly absorbed and peak plasma levels are reached within 0.5-1 hr in rats and 2 hr in dogs. Unchanged premazepam is cleared faster in rats than in dogs, with half-lives about 1.7 and 2.7 hr, respectively. Following oral dosage, two-thirds of the dose is eliminated in urine. From the urine of the two species, eight metabolites and unchanged premazepam were identified. N-7-Desmethyl premazepam (l) is the major metabolite in rat urine (18% of the dose) but is not present in dog urine, while 6-hydroxymethyl premazepam is the most abundant metabolite in dog urine (25% of the dose) but is absent in rat urine. Metabolites III and IV from rat and dog urine are stable derivatives of the intermediate formed by the cleavage of the imine bond of the diazepine ring. A successive hydrolysis of the amidic bond of the same intermediate originates metabolites V-VIII, which are quantitatively minor ones.

Animals↗

PubMedDate not supplied

Metabolism of the neuroleptic agent zetidoline in the rat and the dog.

The metabolism of zetidoline, a new neuroleptic, in the rat and the dog has been studied. From the urine of rats and dogs given 5 mg/kg of [2-14C] zetidoline orally, unchanged drug and five metabolites were isolated and the structures of four of them assigned by physicochemical analysis. They are: metabolite B, 4'-hydroxy-3'-chlorophenyl zetidoline; metabolite D, zetidoline without the aryl group; metabolite E, the 6'-hydroxy-4'-beta-D-glucuronide of metabolite B, and metabolite F, the 4'-beta-D-glucuronide of metabolite B. The plasma levels of zetidoline and its metabolites after iv administration show that the drug is rapidly excreted and/or metabolized in both animal species. The plasma radioactivity in the dog consists mainly of the pharmacologically active (neuroleptic) metabolite B, whereas in the rat it consists of the more polar metabolites. After oral administration, elimination in both species occurs mostly via the kidneys. In the dog, within a 24-hr period, 6.2 +/- 0.4% of the dose is accounted for as unchanged zetidoline, 7.6 +/- 0.5% as metabolite B, 10.1 +/- 0.7% as the unidentified metabolite C, and 21.4 +/- 1.1% as metabolite F. In the rat, over the same period, zetidoline is present in traces, metabolite B accounts for 6.9 +/- 0.3% of the dose, metabolite D for 6.6 +/- 0.9%, metabolite E for 15.2 +/- 1.4%, and metabolite F for 31.7 +/- 2.2%.

Animals↗