Urinary metabolites of felodipine,a new vasodilator drug,in man,dog, rat and mouse

1. The urinary excretion of total ¹⁴C after oral administration of 25 mg (～ 1 μmol/kg) ¹⁴C-felodipine to man, and intragastric administration (5 μmol/kg) to dog, rat and mouse, was 70, 39, 44 and 53% dose, respectively, in 72 h.

2. Metabolites of felodipine were separated and quantified by h.p.l.c. Unchanged felodipine and its oxidized analogue were not excreted by any of the species studies.

3. Three metabolites, present in all species studied, were isolated from urine and identified as products of the oxidation of felodipine to its pyridine analogue followed by hydrolysis of one or both of the pyridine carboxylic acid esters.     

Urinary metabolites of rifabutin, a new antimycobacterial agent, in human volunteers

1. Metabolites of the antimycobacterial agent 4-deoxo-3,4-[2-spiro-(N-isobutyl-4-piperidyl)]-(1H)-imidazo-(2,5-dihydro )- rifamycin S (rifabutin) were isolated from human urine after administration of a single oral dose of the drug. Some of these metabolites were identified by direct inlet mass spectrometry, 1H-n.m.r. spectrometry and, in two cases, by chromatographic comparison with reference compounds. 2. Unchanged drug, 25-O-deacetyl rifabutin and four other metabolites were identified in human urine. 25-O-Deacetyl rifabutin was the main urinary metabolite, other metabolites were characterized as oxidized, and oxidized-deacetylated derivatives. 3. Routes of metabolic transformation were: (a) deacetylation at position 25, (b) oxidation of methyl groups 31 or 32 or at the piperidine nitrogen, and (c) combination of these.     

Metabolic fate of carteolol hydrochloride (OPC-1085), a new beta-adrenergic blocking agent. (6) Pharmacokinetics of carteolol in the rat, dog, rabbit and man]

The kinetics (absorption, distribution and excretion) of carteolol were investigated after oral and intravenous administration to man, rats, Beagle dogs and rabbits. The half-life of carteolol in plasma was 1.22 approximately 1.45 hr in rats, 1.73 approximately 2.08 hr in dogs and 1.42 approximately 1.43 hr in rabbits, and was independent of the route of administration. The absorption rate constants, obtained from log(C1-C) approximately time plot, after oral administration were 1.89 hr-1 in rats, 1.04 hr-1 in dogs and 1.54 hr-1 in rabbits. There were no differences between tablet and film coated tablet in the pharmacokinetic parameters of carteolol in man after oral 30 mg (tablet or film coated tablet) administration [half life (t1/2)=4.50 hr (tablet), 4.30 hr (film coated tablet), elimination rate constant (k2) equals 0.154 hr-1 (tablet), 0.161 hr-1 (film coated tablet)]. The elimination rate constant, obtained from Sigma-minus plot after 2, 5 and 10 mg oral administration, was 0.137 approximately 0.160 hr-1.     

Pharmacokinetics and metabolism of tomoxiprole, a new analgesic antiinflammatory agent, in the rat

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.     

Metabolism of denopamine, a new cardiotonic agent, in the rat and dog

The metabolism of denopamine, (R)-(-)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino] ethanol, a new, orally active, selectively inotropic cardiotonic agent, was studied in the rat and dog. Animals were given single oral doses of 5 mg/kg of denopamine labeled with 14C. Denopamine was metabolized in the rat and dog by several pathways including conjugation, side chain oxidation, and ring hydroxylation followed by O-methylation. Rats excreted the drug in the urine almost entirely as unchanged drug and its phenolic O-glucuronide whereas in the dog, the major metabolites were the phenolic O-glucuronide, the alcoholic O-glucuronide, and the phenolic O-sulfate of denopamine and the phenolic O-glucuronide of 3-methoxydenopamine. Demethylation, which has been shown to be a major metabolic pathway in man, and side chain oxidation were minor pathways in the rat and dog. Furthermore, a high degree of stereoselective resistance of the alcoholic O-glucuronide of denopamine to hydrolysis by beta-glucuronidase was observed.     

Comparative metabolism of codeine in man,rat, dog,guinea-pig and rabbit: identification of four new metabolites

The metabolism and excretion of codeine and its metabolites in untreated urine of man, rat, dog, guinea-pig and rabbit have been examined. Metabolites were identified by gas chromatography mass spectrometry operated in the chemical ionization mode (methane). Concentrations of codeine and metabolites were measured by selected ion monitoring. Both codeine and norcodeine were detected in the urine of all species but a new metabolite, hydrocodone, was found only in the urine from man, guinea-pig and dog. Additional metabolites (presumably resulting from the metabolism of hydrocodone) were also detected in man and guinea-pig. Overall recoveries of drug and metabolites from untreated urine were low for all species.     

In vitro biotransformation of the analgesic agent, RWJ-51784, in rat, dog and human.

RWJ-51784, an analogue of phenyl isoindoles, is a new analgesic agent. The in vitro metabolism of RWJ-51784 was conducted using rat, dog and human hepatic S9 in the presence of an NADPH generating system, and API-ionspray-MS and MS/MS techniques for the metabolite profiling and identification. Unchanged RWJ-51784 (82, 80 & 86% of the sample in rat, dog & human, respectively) plus 6 metabolites were profiled and tentatively identified on the basis of MS data. RWJ-51784 metabolites were formed via the following 3 metabolic pathways: 1. N-demethylation, 2. phenylhydroxylation, and 3. isoindole-oxidation. Pathway 1 produced a moderate or minor metabolite, N-desmethyl-RWJ-51784 (M1; 6% in rat; 5% in dog, 2% in human). Pathway 2 formed 4-hydroxyphenyl-RWJ-51784 (M2; 3-6% in all species). Step 3 formed 2 isoindole-oxidized metaboliotes, OH-indole (M3; 7-8% in all species) and oxo-indole (M4; <1% in all species)-RWJ-51784, and in conjunction with pathway 2 produced 2 trace metabolites, OH-phenyl-OH-isoindole (M5) and OH-phenyl-oxo-isoindole (M6) metabolites. RWJ-51784 is not extensively metabolized in rat, dog and human hepatic S9 fractions.     

Pharmacokinetics of a non-narcotic analgesic,DA-5018, in rats

The pharmacokinetics of a non-narcotic analgesic, DA-5018, were compared after single intravenous (IV), subcutaneous (SC), and oral administrations, and after multiple (seven consecutive days) SC administration to rats. After IV administration of DA-5018, 1, 2, and 5 mg kg⁻¹, the pharmacokinetic parameters of DA-5018 were independent of the dose ranges studied. After oral administration of DA-5018, absorption of the drug from gastrointestinal (GI) tract was fast, but the extent of absolute bioavailability (F) was low; the values were 23.2, 23.0, and 27.3% for 2, 5, and 10 mg kg⁻¹, respectively. After single SC administration of DA-5018, absorption of the drug from the injected site was fast and the extent of absorption was fairly good; the F values were 74.5 and 71.8% for 2 and 5 mg kg⁻¹, respectively. The lower F values after oral administration of DA-5018 to rats could be due to degradation of the drug in rat GI tract and/or considerable first-pass effect. After IV, oral, and SC administration of DA-5018, the drug had a strong affinity to the rat tissues studied as reflected in the greater-than-unity tissue to plasma ratio. After IV, oral, and SC administration of the drug, the biliary and urinary excretion of unchanged DA-5018 were negligible. There was no significant difference in the pharmacokinetics or tissue distribution of DA-5018 between single and multiple SC administration of the drug, 5 mg kg⁻¹, to rats, indicating that there could be no tissue accumulation of the drug after multiple SC administration of the drug to rats. © 1998 John Wiley & Sons, Ltd.     

Comparative metabolism of codeine in man, rat, dog, guinea-pig and rabbit: identification of four new metabolites.

The metabolism and excretion of codeine and its metabolites in untreated urine of man, rat, dog, guinea-pig and rabbit have been examined. Metabolites were identified by gas chromatography mass spectrometry operated in the chemical ionization mode (methane). Concentrations of codeine and metabolites were measured by selected ion monitoring. Both codeine and norcodeine were detected in the urine of all species but a new metabolite, hydrocodone, was found only in the urine from man, guinea-pig and dog. Additional metabolites (presumably resulting from the metabolism of hydrocodone) were also detected in man and guinea-pig. Overall recoveries of drug and metabolites from untreated urine were low for all species.     

Urinary metabolites of benzbromarone in man

Benzbromarone [3,5-dibromo-4-hydroxyphenyl)-(2-ethyl-3-benzofuranyl)-ketone) is a widely used uricosuric drug which was reported to be metabolized by successive debromination. Recently, however, it was reported that benzbromarone is not debrominated but hydroxylated at the ethyl side chain. The presented paper describes further studies on the metabolism of the drug in man. The metabolites were identified in urine samples from two different patients intoxicated suicidally with high doses of benzbromarone after cleavage of conjugates, extraction and derivatization by acetylation using gas chromatography-mass spectrometry. The following five metabolites could be identified besides the unchanged benzbromarone (BB): hydroxy-alkyl-BB, oxo-BB, two isomers of hydroxyaryl-BB and hydroxy-methoxy-aryl-BB. Therefore, the following two phase I metabolic pathways can be postulated: successive oxidation of the ethyl side chain and one- and twofold hydroxylation of the benzofuran ring followed by methylation of one of the hydroxy groups. Benzbromarone and its metabolites are excreted in urine partly in a conjugated form. Debrominated metabolites could not be detected, although the concentrations of benzbromarone and its metabolites were very high in the urine samples studied.     

Pharmacokinetics of a novel surface-active agent,purified poloxamer 188, in rat,rabbit, dog and man

Purified poloxamer 188 (PP188) is a non-ionic, block copolymer surfactant that is currently being evaluated clinically in sickle cell disease vaso-occlusive crisis and acute chest syndrome and preclinically in spinal cord injury and muscular dystrophy. This paper describes the pharmacokinetics of PP188 in rats, pregnant rats, pregnant rabbits, dogs and humans. Plasma protein binding interaction studies demonstrated no clinically significant effects on narcotic analgesics, hydroxyurea, warfarin, diazepam or digitoxin, but an increase in free fraction for propranolol. The plasma concentrations increased proportionate with increasing dose in all species tested. Renal clearance accounted for 90% of total plasma clearance in man. A single metabolite was detected and quantified in the plasma from dogs and humans that was cleared more slowly than parent drug. Allometric scaling of plasma clearance and volume of distribution at steady-state (Vss) across species provided good predictions of the pharmacokinetic parameters in humans. Based on the comparative pharmacokinetics of PP188 in rat, rabbit, dog and man, all three animal species were appropriate models for evaluating various aspects of PP188's toxicological profile.     

Absorption,distribution, metabolism and excretion of cizolirtine,a new analgesic compound,in rat and dog

1. The pharmacokinetics of cizolirtine citrate, a new analgesic compound, were studied in the rat and dog following single oral and intravenous doses. 2. Absorption of radioactivity was fast and complete regardless of the species, and no dose and food-related differences were found. However, the elimination half-life of unchanged cizolirtine was shorter in rat than in dog. 3. Tissue distribution of total radioactivity in rat differed widely and a high affinity for liver, kidney, gastrointestinal and pigmented tissues was observed. In blood and almost all tissues the highest concentrations were reached at 20 min; beyond that time the decline of radioactivity in most tissues was parallel to that in blood. 4. The percentage of radioactivity excreted in the rat was 68% in urine and 21% in faeces, the latter being apparently due to drug enterohepatic circulation. In the dog, 92 and 4% of the radioactivity was found in urine and faeces respectively. The contribution of renal excretion to cizolirtine elimination was 5% in rat and 20% in dog. Twelve metabolites were detected in rat and six in the dog by radio-hplc analysis of urine.     

Formation of identical metabolites from piperazine- and dimethylamino-substituted phenothiazine drugs in man, rat and dog

Degradation of the piperazine ring in the phenothiazine drugs perazine, trifluoperazine, fluphenazine, prochlorperazine and perphenazine in vivo leads to the formation of γ-(phenothiazinyl-10)-propylamine (PPA) and of its ring-substituted analogues CF₃-PPA and Cl-PPA. The sulfoxides of these metabolites have been identified as urinary biotransformation products in patients ingesting perazine or fluphenazine, in rats treated chronically with perazine, trifluoperazine, prochlorperazine or perphenazine, and in a dog given fluphenazine. The structures of the compounds have been confirmed by mass spectrometry. The primary amines are also known metabolites of dimethylamino-substituted phenothiazines, since PPA results from didemethylation of promazine, and CF₃-PPA and Cl-PPA (= nor₂-chlorpromazine) are formed from triflupromazine and chlorpromazine, respectively.     

Absorption, distribution, metabolism and excretion of cizolirtine, a new analgesic compound, in rat and dog.

1. The pharmacokinetics of cizolirtine citrate, a new analgesic compound, were studied in the rat and dog following single oral and intravenous doses. 2. Absorption of radioactivity was fast and complete regardless of the species, and no dose and food-related differences were found. However, the elimination half-life of unchanged cizolirtine was shorter in rat than in dog. 3. Tissue distribution of total radioactivity in rat differed widely and a high affinity for liver, kidney, gastrointestinal and pigmented tissues was observed. In blood and almost all tissues the highest concentrations were reached at 20 min; beyond that time the decline of radioactivity in most tissues was parallel to that in blood. 4. The percentage of radioactivity excreted in the rat was 68% in urine and 21% in faeces, the latter being apparently due to drug enterohepatic circulation. In the dog, 92 and 4% of the radioactivity was found in urine and faeces respectively. The contribution of renal excretion to cizolirtine elimination was <5% in rat and 20% in dog. Twelve metabolites were detected in rat and six in the dog by radio-hplc analysis of urine.