Effect of its demethylated metabolite on the pharmacokinetics of unchanged TAK-603, a new antirheumatic agent, in rats.

A factor in the dose-dependent pharmacokinetics of ethyl 4-(3, 4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2, 4-triazol-1-yl-methyl)quinoline-3-carboxylate (TAK-603) in rats was shown to be due to the inhibition of metabolic clearance of unchanged TAK-603 by its major metabolite, M-I, in other words, product inhibition. The effect of M-I on the metabolic clearance of TAK-603 was studied using rats continuously infused i.v. with this metabolite at rates of 5.3 and 16.0 mg/h/kg. The total body clearance of TAK-603 was decreased remarkably in M-I-infused rats, and the decline of total body clearance depended on the steady-state plasma concentrations of M-I. The effect of M-I generated from the dosed parent drug on the plasma concentration-time profile of TAK-603 was investigated using bile-cannulated rats after i.v. injection of 14C-labeled TAK-603 at doses of 1 and 15 mg/kg. Elimination rates of TAK-603 from rat plasma increased in the bile-cannulated rats in which systemic M-I levels were reduced by interrupting its enterohepatic circulation. To express, simultaneously, the relationships between TAK-603 and M-I in plasma concentration-time profiles, a kinetic model based on the product inhibition was developed for the bile-cannulated rats. A good agreement between calculated curves and the observed concentrations of both TAK-603 and M-I was found at 1 and 15 mg/kg, and the calculated curves were drawn using constant parameters for the two dosages. These results show that the product inhibition by M-I is one factor responsible for the dose-dependent pharmacokinetics of TAK-603 in rats.

Possible factor for nonlinear pharmacokinetics of TAK-603, a new antirheumatic agent, in rats.

A new antirheumatic, TAK-603, shows nonlinear pharmacokinetics in both animals and humans. To elucidate the mechanism of these nonlinear pharmacokinetics, in vivo and in vitro metabolism of 14C-labeled TAK-603 ([14C]TAK-603) was studied using rats as these resemble humans in their metabolic profiles. After intravenous injection of [14C]TAK-603 to rats at doses of 1, 5, and 15 mg kg(-1), the total body clearance of unchanged drug decreased significantly with increasing dose, whereas the apparent distribution volume did not alter remarkably. Thus, saturation in the elimination processes was considered to be a factor responsible for the nonlinear pharmacokinetics. The disappearance of unchanged drug from the circulation, however, followed a dose-dependent first-order process, indicating that the nonlinearity observed was not merely due to saturation of the elimination capacity. In vitro studies using rat liver microsomes showed that TAK-603 competitively inhibited CYP-catalysed nifedipine oxidation and also that the demethylated metabolite M-I, the major metabolite in rats and humans, competitively inhibited the oxidation of nifedipine. These results suggested that inhibition by M-I of the metabolism of the parent drug (i.e. product-inhibition) may be the most likely factor responsible for the nonlinear pharmacokinetics of TAK-603.

Disposition of the new antirheumatic agent ethyl 4-(3,4-dimethoxyphenyl)- 6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylate (TAK-603) in rats and dogs.

The disposition of ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4- triazol-1-ylmethyl) quinoline-3-carboxylate (CAS 158146-85-1, TAK-603) after single oral dosing of 14C-labeled TAK-603 ([14C]TAK-603) at 10 mg/kg to rats and dogs was studied. In rats, the concentration of unchanged drug in plasma reached a peak (Cmax, 0.31 microgram/ml) 2 h (Tmax) after dosing of TAK-603 and declined biphasically with apparent half-lives (t 1/2 alpha, t 1/2 beta) of 1.5 and 3.6 h. In dogs, Tmax, Cmax, T 1/2 alpha, and t 1/2 beta were 1.7 h, 0.36 microgram/ml, 1.2, and 10.8 h, respectively. [14C]TAK-603 dosed orally was absorbed quantitatively in rats, while the extent of absorption in dogs was 54%. The bioavailability of TAK-603 was 53% and 42% in rats and dogs, respectively. In rats, 14C was distributed widely in various tissues, with relatively high concentrations in the liver, adrenal gland, and gut. The elimination of 14C from the thyroid was slower than that from other tissues. Unchanged TAK-603 and its pharmacologically active metabolite, M-I, which has the same potency as TAK-603, were distributed in articular soft tissues and synovial fluids, as target tissues, in rats and dogs, respectively. After oral administration of [14C]TAK-603, most of the 14C dosed was excreted within 48 h in rats and within 96 h in dogs. In both animals, a greater amount of the 14C dosed was excreted in feces than in urine. In biliary duct cannulated rats given [14C]TAK-603 intraduodenally, 69% of the dose was excreted in bile, and biliary 14C in part underwent enterohepatic circulation.

Studies on the metabolism of the new antidiabetic agent pioglitazone. Identification of metabolites in rats and dogs.

Metabolic studies of pioglitazone (CAS 105355-27-9, AD-4833), a new agent, in rats and dogs using liquid chromatography/tandem mass spectrometry and 1H-nuclear magnetic resonance led to characterization of the following metabolites; the parent compound, (+/-)-5-(p-hydroxybenzyl)-2-4-thiazolidinedione (M-I), (+/-)-5-[p-[2-(5-ethyl-2-pyridyl)-2-hydroxyethoxy]benzyl] -2,4-thiazolidinedione (M-II), (+/-)- 5-[p-[2-(5-acetyl-2-pyridyl)ethoxy]benzyl]2,4-thiazolidinedione (M-III), (+/-)-5-[p-[2-[5-(1-hydroxyethyl)-2- pyridyl]ethoxy]benzyl]-2,4-thiazolidinedione (M-IV), (+/-)-5-[p-[2-(5- carboxymethyl-2-pyridyl)ethoxy]- benzyl]-2,4-thiazolidinedione (M-V), and (+/-)-5-[p-[2-(5-carboxy-2- pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione (M-VI). Pioglitazone is considered to be metabolized by cleavage of aliphatic C-O bond to lead to M-I, hydroxylation of aliphatic methylene groups to form M-II and M-IV, oxidation of M-IV to give M-III, oxidation of the ethyl group to form M-V, and oxidative loss of the terminal carbon to lead to M-IV. Furthermore, part of metabolites exist as conjugated form. Among the conjugates, M-IV conjugated with sulfuric acid and M-V conjugated with taurine were identified.

Disposition of the new antidiabetic agent pioglitazone in rats, dogs, and monkeys.

The disposition of pioglitazone (CAS 105355-27-9, AD-4833) was studied after oral administration to rats, dogs, and monkeys using 14C-labeled drug. After oral dosing, pioglitazone was well absorbed from the gastrointestinal tract at an extent of 96, 95, and 90% in rats, dogs, and monkeys, respectively. In rats, the concentration of pioglitazone in plasma reached a peak (Cmax 0.71 micrograms/ml) at 4 h (tmax) after dosing and declined with a half-life (t1/2) of 2.6 h. In dogs, tmax, Cmax and t1/2 were 0.5 h 0.32 micrograms/ml and 2.1 h, and those for monkeys were 4.3 h, 0.43 micrograms/ml and 5.3 h, respectively. The drug was metabolized mainly to M-I to M-VI including the pharmacologically active metabolites (M-II, III and IV). The pharmacologically active compounds (total of the unchanged compound and the above three active metabolites) accounted for 87, 71, and 73% of the radioactivity in plasma of rats, dogs and monkeys, respectively. The radioactivity was widely distributed in tissues after oral administration to rats, and decreased to the very low concentration within 24 to 72 h after dosing. Radioactivity dose was almost completely excreted in urine and feces.

Absorption of the anxiolytic pazinaclone in animals as a criterion for species selection for toxicity studies.

In rats, mice, hamsters, and guinea pigs given a 5 mg/kg oral dose of pazinaclone (CAS 103255-66-9), unchanged drug concentration in plasma was highest in mice (AUC; 90 ng.h/ml), followed in decreasing order by guinea pigs (AUC; 41 ng.h/ml), hamsters (AUC; 18 ng.h/ml), and rats (AUC; 17 ng.h/ml). In terms of plasma drug concentrations and toxicological background data, there was no better alternative rodents than mice and rats for the toxicity studies. Among rabbits, dogs, and monkeys, the dogs had the highest plasma drug concentrations: AUCs of pazinaclone in dogs and monkeys were 1035 and 458 ng. h/ml, respectively (drug concentration in rabbit plasma was very low). Of the two polymorphs, forms 1 and 2 with particle size of < or = 5 microns, the oral absorption of form 2 in rats was more efficient than that of form 1 at 1000 mg/kg: AUCs of pazinaclone after dosing of form 1 and 2 were 489 and 965 ng.h/ml, respectively. However, form 1 was selected for the toxicity studies because of the poor physico-chemical properties of forms 2. Form 3 was not included in this study, because this form was relatively unstable and contained relatively large amount of impurities. The absorption of pazinaclone in dogs was improved by decreasing its particle size: AUCs of pazinaclone after dosing of the drug having particle size of 5.5, 20.8, and 79.3 microns were 1361, 822, and 297 ng.h/ml, respectively. Since large-scale preparation of bulk pazinaclone with a particle size of 5 microns or smaller was not feasible, the drug having a particle size of about 20 microns was used in the toxicity studies. The absorption of pazinaclone was more extensive when the drug was given to fed animals as suspension. Thus, the toxicity studies were performed using form I of pazinaclone with a particle size of about 20 microns primarily in rats, mice, and dogs.

Bioactive metabolites of EM574 and EM523, erythromycin derivatives having strong gastrointestinal motor stimulating activity.

Two motilides, EM574 (N-demethyl-N-isopropyl-8,9-anhydroerythromycin A 6,9-hemiacetal) and EM523 (N-demethyl-N-ethyl-8,9-anhydroerythromycin A 6,9-hemiacetal) have strong gastrointestinal motor stimulating (GMS) activity. When administered orally to dogs, these agents showed strong GMS activity, but their plasma levels were very low and the metabolites which have been determined so far using the radio-labeled compounds show only weak GMS activity. The findings suggested that unknown bioactive metabolites might be responsible for the GMS activity. From the liver of dogs given EM574 intravenously, two bioactive metabolites, EM574 P1 and P2, were isolated by solvent extraction and chromatography as detected by contractile activity. They both showed the same UV spectra as EM574 and the molecular ion peaks at m/z 760 (MH+) and 602 (MH(+)-cladinose) in the FAB-MS. From 2D-NMR experiments, the structures of EM574 P1 and P2 were unveiled to be the 15- and 14-hydroxyl derivatives of EM574, respectively. EM523 P1 and P2 were also isolated in the same procedure. In order to prepare these bioactive metabolites, EM574 and EM523 were converted enzymatically with dog liver homogenates in the presence of co-enzymes to give the corresponding P1 and P2. The structures of the metabolites are shown in Fig 1. They exhibited stronger contractile activity in vitro and GMS activity in vivo than the parent compounds.

Characterization of conjugated metabolites of a new angiotensin II receptor antagonist, candesartan cilexetil, in rats by liquid chromatography/electrospray tandem mass spectrometry following chemical derivatization.

Combined liquid chromatography and electrospray mass spectrometry (LC/ESI-MS) and tandem mass spectrometry (MS/MS) were used for the characterization of the conjugated metabolites (glucuronides) of a new angiotensin II receptor antagonist, candesartan cilexetil (TCV-116; (+/-)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-¿[2'-(1H-tetrazol-5-yl)biphenyl- 4-yl]methyl¿-1H-benzimidazole-7-carboxylate) in the plasma and bile of rats given the drug. The glucuronides of the active component, M-I (candesartan), in rat plasma and bile were positional isomers with respect to the binding site of glucuronic acid. The site of glucuronidation in M-I was not directly identified by mass spectrometry. However, the structure of the isomers could be elucidated by the MS/MS analysis of dimethylated glucuronides prepared by the reaction of glucuronide isomers with diazomethane: N-glucuronide of M-I (M-I-NG) in the plasma and acyl glucuronide (M-I-AG) in the bile. The results obtained in this study indicated that LC/ESI-MS/MS analysis provides the detailed structure of conjugated metabolite by simple chemical derivatization.

Disposition of the new angiotensin II receptor antagonist candesartan cilexetil in rats and dogs.

The disposition of candesartan cilexetil (CAS 145040-37-5, TCV-116) was studied after oral administration of 14C-labeled drug to rats and dogs. Candesartan cilexetil was absorbed from the small intestine and hydrolyzed completely to the pharmacologically active metabolite M-I during absorption process. In the plasma of these animals, an appreciable amount of M-I was present with no detectable concentration of unchanged drug. The M-I concentration in rat plasma attained a peak (Cmax, 0.280 microgram/ml) 2.3 h (Tmax after dosing and then declined with an apparent half-life (t1/2) of 3.8 h. In dogs, Tmax, Cmax, and t1/2 of M-I were 1.3 h, 0.012 microgram/ml, and 4.3 h, respectively. The bioavailabilities of M-I in rats and dogs were 28 and 5%, respectively. M-I was distributed widely in the tissues including the blood vessels as target tissues, was metabolized partially to the glucuronide and M-II, and was eliminated predominantly into the feces via biliary excretion. The elimination of M-I from the blood vessels was slower than that from the plasma. The sustained antihypertensive effect of this drug seemed to be due to the slow elimination of M-I from the blood vessels. With daily oral dosing for 14 days, no appreciable amounts of drug-related compounds were accumulated in rat body.

Enantiomeric toxicokinetics of the new isoindoline anxiolytic pazinaclone in rats and dogs.

Enantiomeric toxicokinetics of the new isoindoline pazinaclone (CAS 103255-66-9, DN-2327) were studied in rats and dogs of both sexes after oral administration by gavage. Non-toxic doses in 4-week toxicity studies in rats are > or = 3000 mg/kg/d and 500 mg/kg/d for S- and R-pazinaclone, respectively; the corresponding doses in dogs are 10 and 4 mg/kg/d, respectively. R-Pazinaclone is more toxic in female rats than in male rats. In both rats and dogs, circulating enantiomer concentrations of pazinaclone and the active M-II metabolite increased with dose. Higher S- and R-pazinaclone concentrations were found in female rats than in male rats; the concentrations in dogs were sex independent. In rats, the AUCs for the parent compound after a 3000 mg/kg oral dose of S-pazinaclone were about 9-fold (males) and 4-fold (females) greater than those after dosing of R-pazinaclone at 500 mg/kg. In dogs, the AUC for the parent compound after a 10 mg/kg oral dose of S-pazinaclone was 33-fold greater than that after oral dosing of the R-enantiomer at 4 mg/kg. The toxic activity is thus likely to reside predominantly in the R-enantiomers of pazinaclone and M-II. The exposure of the R-enantiomers in humans, after administration of the anticipated clinical dose of the racemic drug, seemed to be no more than that in rats and dogs at nontoxic doses.

Enantioselective pharmacokinetics in animals of pazinaclone, a new isoindoline anxiolytic, and its active metabolite.

The enantioselective pharmacokinetics of a new anxiolytic, pazinaclone (DN-2327), and its active metabolite, M-II, were studied in animals. In rats and dogs given racemic pazinaclone intravenously, the total clearance and volume of distribution of (S)-pazinaclone were lower than those of (R)-pazinaclone, whereas the opposite results were obtained in monkeys. The differences in disposition were consistent with enantioselective protein binding, where the unbound fraction was greater for (R)-pazinaclone than that for the (S)-enantiomer in rats and dogs; the reverse was noted in monkeys. Lower clearance and distribution for (S)-pazinaclone in rats and dogs, and for the (R)-enantiomer in monkeys, resulted in comparable plasma profiles for the pazinaclone enantiomers and thereby those of the corresponding enantiomers of M-II. The unbound clearance (CLu) of (S)-pazinaclone was, however, greater than that of the antipode in rats and dogs and the CLu of each enantiomer was similar in monkeys. Thus, enantioselectivity in the kinetics of (S)- and (R)-pazinaclone appears to reside largely in plasma binding differences and is unrelated to variations in intrinsic clearance. The first-pass metabolism of (S)- and (R)-pazinaclone on oral administration of the racemate was enantioselective, with respective bioavailabilities of 1.7 and 0.8% in rats, 10.4 and 1.9% in dogs, and 0 and 11.4% in monkeys. Therefore, the enantioselectivity was more pronounced after oral dosing.

Enantioselective determination of pazinaclone, a new isoindoline anxiolytic, and its active metabolite in rat plasma by high-performance liquid chromatography.

A sensitive and specific high-performance liquid chromatographic method has been developed for the simultaneous determination of the enantiomers of pazinaclone (DN-2327), a new anxiolytic agent, and those of its active metabolite, M-II, in rat plasma. Organic solvent extraction of pazinaclone, M-II, and internal standard (I.S.) in plasma was followed by separation of the analytes from other metabolites using an achiral reversed-phase column. Fluorescence detection was employed with excitation and emission wavelengths of 328 and 367 nm, respectively. Separation of all the enantiomers and I.S. was then accomplished with normal- and chiral-phase columns connected in series. For each analyte, the lower quantitation limit was 0.5 ng/ml. The assay has been applied to a chiral inversion study in rats. Chiral conversion from one enantiomer of pazinaclone to the other hardly occurred. This method is suitable for enantioselective pharmacokinetic and toxicokinetic studies in animals.

Analysis of dog and rat plasma for metabolites of a new isoindoline anxiolytic, DN-2327, by liquid chromatography/thermospray mass spectrometry and tandem mass spectrometry.

Combined liquid chromatography/thermospray mass spectrometry (full scan) and its tandem mass spectrometry (precursor ion, product ion and neutral loss scan) were used to characterize rat and dog plasma metabolites of an anxiolytic candidate (DN-2327; (+-)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-[(1,4-dioxa-8- azaspiro[4.5]dec-8-yl)carbonylmethyl]isoindolin-1-one) . The results indicated that DN-2327 was metabolized to M-I by hydrolysis of the dioxolane ring which was subsequently reduced at the carbonyl moiety to form M-II. M-II was further metabolized to diol isomers, M-III and M-IV, by hydroxylation on the hydroxypiperidine moiety. M-V was an acyclic diol resulting from cleavage of the piperidine ring followed by reduction of the aldehyde. By the methodology used here, detailed structural information could be obtained without recourse to individual metabolite isolation and this provided a great saving in time and effort.

Brain distribution of idebenone and its effect on local cerebral glucose utilization in rats.

To investigate the possible action sites of a cerebral metabolism activator, idebenone, (6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone), its distribution in the brain and effect on local cerebral glucose utilization (LCGU) were studied in normal (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) with cerebrovascular lesions. 14C-Idebenone distributed rapidly into the brain after intravenous administration (10 mg/kg), and the total 14C contents in the brain at peak time corresponded to 0.45-0.56% of the dosages. An autoradiographic study showed that the 14C levels were higher in the white than in the gray matter. When 14C-idebenone was administered orally (100 mg/kg) and intraperitoneally (30 mg/kg), the total 14C levels were not markedly different among the brain regions of the rats. The concentration of unchanged idebenone was higher in the cerebral cortex, thalamus, and cerebellum than that in the other brain regions. Studies on LCGU demonstrated that idebenone (30 mg/kg/day, i.p., for 3 days) improved the reduction of LCGU in SHRSP with stroke, especially in the temporal cortex, thalamus dorsomedial nucleus, subthalamic nucleus, mamillary body, hippocampus dentate gyrus, caudate-putamen, inferior colliculus, and cerebellar nucleus. Based on these results, possible action sites of idebenone for its main pharmacologic effects are discussed.

Metabolism and disposition of (RS)-2-methoxy-3-(octadecylcarbamoyloxy)propyl 2-(3-thiazolio)ethyl phosphate (MOTP) in rats and dogs.

1. Metabolites (RS)-4-[(3-hydroxy-2-methoxy)propoxycarbonylamino]butanoic acid (I) and (RS)-2-[(3-hydroxy-2-methoxy)propoxycarbonylamino]acetic acid(II) were isolated from urine after i.v. administration of (RS)-2-methoxy-3-(octadecyl-[14C]carbamoyloxy)propyl 2-(3-thiazolio)ethyl phosphate (14C-MOTP) to rats and characterized by t.l.c., g.l.c.-mass spectrometry and p.m.r. spectrometry. 2. After i.v. administration of 14C-MOTP, the plasma concentration of the drug declined biphasically with half-lives of 0.22 and 3.94 h in rats, and 0.81 and 8.00 h in dogs. In rats and dogs, unchanged MOTP was the main 14C component in the plasma, together with a small amount of I and II. 14C-MOTP was highly bound to plasma protein of both animals. 3. Five min after i.v. administration of 14C-MOTP to rats, 14C was widely distributed in tissues, with the highest conc. in the lung and the lowest in the eye. The distribution of 14C was relatively slow in some tissues. In most tissues, 14C decreased to low levels at 96 h, except in the Harder's gland. 4. Elimination of 14C-MOTP was almost complete within 120 h in rats and 144 h in dogs. In both species, the administered 14C was excreted largely in the urine as I and II, with the remainder appearing in the faeces and the expired air. Biliary excretion and reabsorption of 14C were detected in rats. 5. During repeated i.v. administration of 14C-MOTP to rats for 7 days, the conc. of 14C in plasma and most tissues attained steady state within 5 days, except in Harder's gland, where the level rose gradually until the seventh day of dosing. Within 6 days after the last dosing, 96% of the injected dose was eliminated from the body.

[Brain distribution of idebenone (CV-2619) and its effect on local cerebral glucose utilization in rats].

To investigate the possible action-sites of a cerebral metabolism activator, idebenone (CV-2619), its distribution in the brain and effect on local cerebral glucose utilization (LCGU) were studied both in normal rats (WKY) and in stroke-prone spontaneously hypertensive rats (SHRSP) with cerebrovascular lesions. At 5 min after intravenous administration of [14C] CV-2619 (10 mg/kg), the distribution ratio in the brain was 0.45-0.56% of the dosage. Autoradiographic study showed that 14C levels were higher in the white matter than in the grey matter. When [14C] CV-2619 was administered orally (100 mg/kg) and intraperitoneally (30 mg/kg), 14C levels in eleven brain regions (15 min after administration) were 0.22-0.39 microgram/g (CV-2619 equivalent) and 1.11-1.30 micrograms/g, respectively, in WKY and 0.17-0.28 microgram/g and 1.66-1.87 microgram/g, respectively, in SHRSP. Total 14C levels were not markedly different among the brain regions of the rats. The analysis of unchanged CV-2619 and its metabolites revealed that unchanged CV-2619 in the cerebral cortex, thalamus and cerebellum was relatively higher than that in the other brain regions. Studies on LCGU demonstrated that CV-2619 (30 mg/kg/day, i.p., for 3 days) improved the decrement of LCGU in the temporal cortex, thalamus dorsomedial nucleus, subthalamic nucleus, mamillary body, hippocampus dentate gyrus, caudate-putamen, inferior colliculus and cerebellar nucleus of SHRSP with stroke. Based on these results, the possible action-sites of CV-2619 for its main pharmacological effects were discussed.

Disposition of carumonam (AMA-1080/Ro 17-2301), a new N-sulfonated monocyclic beta-lactam, in rats and dogs.

Rats and dogs were given a single 20-mg/kg dose of [14C]carumonam intramuscularly or intravenously. In rats, the level in plasma of [14C]carumonam administered intramuscularly peaked (29.1 micrograms/ml) 15 min after dosing and then declined with an apparent elimination half-life of 16.2 min. Intramuscular injection of [14C]carumonam to dogs gave a peak level (36.8 micrograms/ml) in plasma at 20 min and an apparent elimination half-life of 51.7 min. After administration of the intravenous dose, apparent elimination half-lives were 13.1 and 52.7 min in rats and dogs, respectively. In both animals, the radioactivity in plasma was made up largely (greater than 80%) of unchanged carumonam, which was protein bound to only a small extent. In rats given [14C]carumonam intramuscularly, radioactivity was distributed widely in tissues, with relatively high concentrations in the kidney and liver. The radioactivity concentration in the rat fetus was relatively low, as was that in milk. In both rats and dogs carumonam did not undergo extensive metabolism; the most prominent metabolite was AMA-1294, the compound resulting from beta-lactam ring hydrolysis. [14C]carumonam and metabolites were mostly eliminated from the bodies within 72 h in rats and 120 h in dogs. In both animals, a large amount of the dosed radioactivity was excreted in the urine largely as unchanged antibiotic. The remainder was eliminated in the feces via bile. AMA-1294 was eliminated from the bodies of rats and dogs at a considerably slower rate than was unchanged carumonam. In rats, [14C]carumonam was eliminated by both glomerular filtration (67%) and tubular secretion (33%); the renal elimination of [14C]AMA-1294 was only by glomerular filtration.

Metabolism of ipriflavone (TC-80) in rats.

Metabolic studies of ipriflavone (TC-80) in rats by gas-liquid chromatography-mass spectrometry led to the characterization of the following metabolites: the parent compound, 7-hydroxy-3-phenyl-4H-1-benzopyran-4-one, 7-hydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one, 3-(4-hydroxyphenyl)-7-isopropoxy-4H-1-benzopyran-4-one, 2-(3-phenyl-4-oxo-4H-1-benzopyran-7-yl)oxypropionic acid, 2-[3-(4-hydroxyphenyl)-4-oxo-4H-1-benzopyran-7-yl]oxypropionic acid and 2-[3-(3-hydroxyphenyl)-4-oxo-4H-1-benzopyran-7-yl]oxypropionic acid. From the metabolites identified, TC-80 was shown to be metabolized primarily by oxidation. In vitro study using tissue slices of rats indicated that the above metabolic changes occurred exclusively in the liver. It was also demonstrated that the compound did not undergo metabolic conversion by gut flora of rats.

Disposition of ipriflavone (TC-80) in rats and dogs.

Oral 14C-ipriflavone was absorbed by rats to give a maximum plasma 14C level at 1.5 h and a half-life of 5.8 h. In dogs, after po dosing, the plasma 14C peaked at 0.5 h, followed by gradual decline. The plasma of both animals contained mostly metabolites, with small amounts of unchanged ipriflavone. In rats, 14C was distributed widely in tissues, with relatively high concns. in the liver, kidney and gut. Distribution in rat thigh bone of unmetabolized ipriflavone was also demonstrated. 14C-Ipriflavone was eliminated mostly as metabolites within 48 and 72 h, respectively, in rats and dogs. Rats excreted more 14C in urine than in feces, whereas the reverse was noted in dogs. Biliary excretion and reabsorption of 14C were also obvious in both animals.

Metabolism of idebenone (CV-2619), a new cerebral metabolism improving agent: isolation and identification of metabolites in the rat and dog.

Metabolic studies of idebenone (CV-2619), a new cerebral metabolism improving agent, in the rat and dog by thin-layer chromatography, gas-liquid chromatography-mass spectrometry and fast atom bombardment-mass spectrometry led to characterization of the following metabolites: the parent compound, 6-(9-carboxynonyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (QS-10), 6-(7-carboxyheptyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (QS-8), 6-(5-carboxypentyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (QS-6), 6-(3-carboxypropyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (QS-4), 1- or 4-phenyl sulfate of the hydroquinone derivatives of CV-2619 and QS-4, and 1- and 4-phenyl glucuronides of the hydroquinone derivative of QS-10. These results indicated that CV-2619 was metabolized by oxidation of the side chain followed by beta-oxidation to form successively QS-10, QS-8, QS-6 and QS-4, and reduction of the quinone ring and subsequent conjugation yielding the sulfates and glucuronides of the hydroquinone derivatives of CV-2619, QS-10, QS-8, QS-6 and QS-4.