Inhibitory effect of indomethacin farnesil, a novel antiinflammatory prodrug, on carrageenin-induced inflammation in rats

Antiinflammatory effects of indomethacin farnesil (IMF), a novel prodrug of indomethacin, was examined after both oral and local administration. In the air pouch carrageenin-induced inflammation, an oral dose of IMF exerted dose dependent inhibitory effects on the accumulation of inflammatory exudate fluid and the migration of leukocytes into the exudate. Both the increased vascular permeability and the prostaglandin E2 levels in the exudate fluid were reduced by IMF. Significant levels of free indomethacin were detected in the pouch fluid. In spite of the inability of IMF to inhibit prostaglandin synthesis in a cell free cyclooxygenase system, IMF injected locally inhibited carrageenin paw edema, and the inhibitory effect was comparable to that of indomethacin itself. When injected locally into the paw together with carrageenin, 14C-IMF was effectively converted to its active metabolite, indomethacin. The indomethacin concentration in the paw tissue was comparable to that of indomethacin injected paws with the same molar dose of free indomethacin.     

Influence of indometacin farnesil on blood coagulation. Comparison with indomethacin in normal rats and warfarin induced hypoprothrombinemic rats

The influence of indometacin farnesil (IMF), a prodrug of indomethacin, on blood coagulation was compared with indomethacin (Ind) in normal rats and warfarin treated rats. In normal rats, 30 mg/kg of Ind very markedly shortened the extrinsic coagulation time and decreased the hematocrit, GOT, GPT and ALP in plasma at 24 hr after administration, but 3 mg/kg of Ind and both 10 and 100 mg/kg of IMF did not influence any parameter. In warfarin treated rats, 2.5 mg/kg of Ind decreased the normal prothrombin level at 48 hr, and 10 mg/kg of Ind prolonged the blood coagulation time, decreased the normal prothrombin level and hematocrit, and increased the PIVKA-II level. Moreover, at 48 hr, 3 of 6 rats in the 10 mg/kg Ind-administered group died due to intestinal bleeding. IMF at all dosages examined did not affect any of the above parameters.     

Metabolic fate of strychnine in rats

1. The urinary and faecal excretions of radioactivity, in rats dosed with 3H-strychnine at 0.5 mg/kg subcutaneously, were approx. 30% and 65% of the dose in 7 days, respectively. The radioactivity was mostly excreted within 24 h. 2. Approx. 6% and 3% dose was excreted into urine and faeces, respectively, as unchanged strychnine. 3. Urinary metabolites were extracted from rat urine and purified by silica gel column, t.l.c. and h.p.l.c. Six urinary metabolites, namely, strychnine N-oxide, 21 alpha,22 alpha-dihydroxy-22-hydrostrychnine, 21 alpha,22 beta-dihydroxy-22-hydrostrychnine, 2-hydroxy-strychnine, strychnine 21,22-epoxide and 16-hydroxystrychnine, were identified by comparison with authentic samples by g.l.c.-mass spectrometry. The major metabolites of strychnine in vivo was strychnine 21,22-epoxide.     

Metabolic fate of bufalin in rats]

In an attempt to evaluate the metabolic fate of "Kyushin", which is a traditional medicine containing Toad venom, a 3H-labeled compound of bufalin, which is one of the main active components, has been synthesized. The metabolic fate of the 3H-bufalin was studied after its single and repeated oral administration in rats. After a single administration of the 3H-bufalin (20 micrograms/kg), the radioactivity in the blood reached a maximum level at 15 min. The radioactivity in the blood declined in a triphasic manner with half-life times of 18 min, 2.6 and 86 h. Within 24 h after the single administration, the excretion of the radioactivity into the urine and feces amounted to 1.3% and 81% of the administered dose, respectively. Tissue radioactivity was higher in the stomach, small intestine, liver, lung, kidney and pancreas, while the radioactivity in other tissues was lower than that in blood. Radioactivity disappeared rapidly from any tissues. In case of repeated administration for 14 d, the disposition of radioactivity was almost same as the result after a single dosing, and radioactivity scarcely remained in any tissues after the last administration.     

Metabolic fate of indeloxazine hydrochloride: alpha-glucoside formation in rats

1. After oral administration of indeloxazine hydrochloride ((+/-)-2-[(inden-7-yloxy)methyl]morpholine hydrochloride) to rats, two conjugates, which were labile to alpha-glucosidase hydrolysis but refractory to beta-glucosidase, were isolated from the urine. 2. Mass spectral and n.m.r. analyses confirmed that these conjugates were alpha-D-glucopyranosides of M-2 (trans-4-(2-morpholinylmethoxy)-1,2-indandiol) and M-3 (trans-6-[[(1,2-dihydroxy-4-indanyl)oxy]-methyl]-3-morpholinone). 3. These are probably the first examples of foreign compounds conjugated with glucose in the alpha-configuration.     

Metabolic fate of the oral hypoglycaemic agent, midaglizole, in rats

1. The metabolic fate of midaglizole, 2-[2-(4,5-dihydro-1H-imidazole-2-yl)-1-phenylethyl]pyridine dihydrochloride sesquihydrate, was studied in rats after a single oral dose of 10 mg/kg. 2. After oral administration of 14C-midaglizole to rats, 63% of the dose was excreted in the urine and 41% in the faeces within 72 h. The major radioactive compound in the urine was unchanged midaglizole and accounted for 38.1% of the dose. In the faeces, two major radioactive compounds, M-VII and unchanged midaglizole, were present. These accounted for 17.2 and 14.1% of the dose, respectively. M-VII is a new metabolite, identified as 2-[2-(4,5-dihydro-1H-imidazole-2-yl)-1-(4-hydroxyphenyl)ethyl]pyridine by n.m.r. and mass spectrometry. 3. The biliary excretion of the radioactivity after oral administration of 14C-midaglizole to bile-duct cannulated rats amounted to 53% of the dose. Of the total amount of radioactivity excreted in the bile, 48% was calculated to be subject to enterohepatic recycling. 4. Four biliary metabolites were new metabolites and were identified by n.m.r., mass spectrometry and enzymic hydrolysis. These compounds are 2-[2-(4,5-dihydro-1H-imidazole-2-yl)-1-(4-hydroxyphenyl)-ethyl]pyridine O-glucuronide (M-XI), 2-[2-(4-hydroxyphenyl)-2-(2-pyridyl)]ethyl-2-imidazole O-glucuronide (M-XII),3-(4-hydroxyphenyl)-3-(2-pyridyl)propioimidamide O-glucuronide (M-XIII) and 2-[2-(4,5-dihydro-1H-imidazole-2-yl)-1-(4-hydroxy- 3-methoxyphenyl)ethyl]pyridine O-glucuronide (M-XIV). These glucuronides accounted for 35.4% of the dose. 5. Midaglizole was metabolized in rats mainly via phenyl ring para-hydroxylation followed by glucuronidation, with or without the biotransformation of the imidazoline ring moiety.     

Metabolic fate of 125I-labeled batroxobin in rats and dogs

125I-Labeled batroxobin was prepared and following its intravenous and subcutaneous administrations to rats and dogs, the blood radioactivity was determined. In the both species following the intravenous injections, the decrease in radioactivity was biexponential. Following subcutaneous administration, radioactivity became maximal at 6h and decreased in a manner similar to that of the beta-phase of the intravenous injection. The blood concentration of fibrinogen in dogs was also determined. After the intravenous injection, fibrinogen became undetectable 1h later, and appeared again in the blood at 24h. After the subcutaneous injection, the decrease was not so rapid. Fibrinogen resumed its original levels at 7 day after the administration in both the routes. Radioactivity after the both injections was excreted generally in the urine in about the same amounts. The total urinary and fecal excretions in rats and dogs were 80 and 95%, respectively. The distribution of radioactivity in the tissues was examined by counting technique and whole-body autoradiography. Radioactivity predominantly accumulated in the thyroid and stomach and could also be found in the kidneys and liver in fair amounts. The distribution patterns of radioactivity for both the routes of administrations and also for male and pregnant rats were basically the same. In fetus rats, a slight distribution was noted. From the results of gel filtration chromatography and trichloroacetic acid fractionation, [125I] batroxobin was metabolized soon after the administration to afford low molecular substances such as 125I-ion in the plasma and urine.     

Metabolic fate of gallic acid orally administered to rats

The metabolic behavior of orally administered gallic acid was investigated by HPLC and 4-O-methyl gallic acid was found to be the main metabolite in rat peripheral blood and urine. After oral administration of gallic acid, maximum concentration in portal vein and inferior vena cava occurred at 15 and 30 min, respectively. In portal vein, gallic acid was preferentially detected relative to 4-O-methyl gallic acid, whereas gallic acid and 4-0-methyl gallic acid were equally detected in inferior vena cava. On the other hand, 4-O-methyl gallic acid but not gallic acid was found in liver. The contents of gallic acid and 4-O-methyl gallic acid in urine were nearly 100 times higher than those in blood. The ratio of 4-O-methyl gallic acid to total gallic acid metabolites in urine was from 0.55 to 0.76, indicating that a considerable amount of gallic acid was excreted without being metabolized. In this study we found that gallic acid administered orally existed in the blood for 6 h at most, and more than half was metabolized to 4-O-methyl gallic acid, followed by excretion into urine.     

Metabolic fate of alclometasone dipropionate in rats, rabbits, and mice. Metabolic products and pathway following subcutaneous administration

The metabolic fate of alclometasone dipropionate (ADP or S-3460) has been studied in rats, rabbits, and mice, with consideration of their interspecies differences. Several reference compounds related to ADP were synthesized for the determination and identification of the metabolites. After sc administration of 14C-labeled ADP, the metabolites in plasma, bile, and urine were separated and analyzed using TLC-ARG (autoradiography) and HPLC in comparison with the reference compounds. The metabolites identified, fully or tentatively, by MS and 1H-NMR totaled 11. The metabolic transformations were: hydrolysis of the side chain esters, dehydrochlorination leading to the formation of delta 6-double bond, 6 beta-hydroxylation, 6 beta, 7 beta-epoxides from 6 beta-hydroxylated metabolites, side chain oxidation to 21-oic and 20-oic acids in the 6 beta-hydroxylated metabolites, and conjugation to glucuronides and sulfates. The metabolic pathway, postulated on the basis of the identified and quantitated metabolites, was a rapid hydrolysis of 21-ester of ADP to the corresponding alcohol, M-1, after systemic uptake. This M-1 was a main metabolite in plasma of animals studied, and due to its relatively longer life time in the media, it seemed to allow a variety of metabolism to occur, giving the oxidative and conjugative metabolites mentioned above.     

Metabolic fate of zetidoline,a new neuroleptic agent,in man

Summary Healthy volunteers administered orally a single dose (20 mg) of [2-¹⁴C]zetidoline, a new dopamine antagonist, exhibited rapid absorption of radioactivity with peak plasma levels of 250–300 ng/ml achieved in 1 h. The compound underwent intensive metabolic first-pass so that plasma radioactivity was represented mostly by two products, metabolite B endowed with neuroleptic activity, and metabolite D inactive, while unchanged zetidoline was not detected. Disappearance of radioactivity from plasma was rapid with a half-life of 1.78±0.20 h.The simultaneous assay of plasma prolactin showed increased levels of the hormone (+464% at the peak time) up to the 6th h after dosing, with plasma concentration profile which mimic those of metabolite B.The radioactive test-dose was eliminated mainly via the kidneys with an average urinary recovery of 84.7±1.7% in 4 days (73.4±1.1% within 8 h). The main urinary metabolite (metabolite G) and two minor ones (metabolites B and D) were purified and their structures assigned by IR, MS and NMR spectroscopy, they are: 1-(3-chloro-4-hydroxyphenyl)-3[2-(3,3-dimethyl-1-azetidinyl)ethyl]imidazolidin-2-one, metabolite B; 1-[2-(3,3-dimethyl-1-azetidinyl)ethyl]imidazolidin-2-one, metabolite D and the 4-O-sulphate ester of metabolite B, metabolite G.The metabolic fate of zetidoline in man follows the same phase I reactions demonstrated in rats and dogs, while the phase II reaction is sulphoconjugation instead of the glucuronidation observed in animals.     

Metabolic fate of injected radiolabelled dopamine and 2-fluorodopamine in rats

In evaluating positron-emitting analogs of dopamine (DA) as possible imaging agents for visualizing tissue sympathetic innervation and function, the metabolic fate of systemically injected [3H]-DA or [14C]-DA was compared with that of [3H]-2-fluoroDA in plasma and in sympathetically innervated tissues (left ventricle, spleen and salivary glands) of rats. By 60 min after the injection of [3H]-DA or [3H]-2-fluoroDA, concentrations of [3H]-DA. [3H]-2-fluoroDA, [3H]-norepinephrine ([3H]-NE) and [3H]-2-fluoroNE in tissue exceeded concentrations in plasma by up to several thousand-fold. Whereas most of the radioactivity in tissue was in catechols, radioactivity in plasma was due to O-methylated metabolites of DA, including homovanillic acid (HVA) and of NE, including normetanephrine (NMN) and methoxyhydroxphenylglycol (MHPG). Estimated ratios of tissue: blood radioactivity at 60 min after injection of [3H]-2-fluoroDA were 4.10 for the heart, 1.91 for the spleen and 2.10 for the salivary glands. The patterns of levels of catechol metabolites and analogs of HVA in plasma and effects of blockade of neuronal uptake with desipramine suggested that [3H]-2-fluoroDA was not as efficiently removed by neuronal uptake and not as efficiently beta-hydroxylated as the non-fluorinated compound. Concurrent administration of [3H]-DA and large amounts of non-radioactive 2-fluoroDA did not substantially alter the pattern of metabolites of [3H]-DA in plasma. After injection of [18F]-fluoroDA, visualization of sympathetic innervation of tissue should be feasible by position emission tomography.     

Metabolic fate of menthofuran in rats. Novel oxidative pathways.

Metabolic fate of menthofuran (II) in rats was investigated. Menthofuran (II) was administered orally (200 mg/kg of the body weight/day) to rats for 3 days. The following metabolites were isolated from the urine of these animals: p-cresol (VI), 5-methyl-2-cyclohexen-1-one (VII), 3-methylcyclohexanone (VIII), 3-methylcyclohexanol (IX), 4-hydroxy-4-methyl-2-cyclohexen-1-one (V), geranic acid (XI), neronic acid (XII), benzoic acid (XIII), and 2-[2'-keto-4'-methylcyclohexyl]propionic acid (X). Incubation of menthofuran (II) with phenobarbital-induced rat liver microsomes in the presence of NADPH and oxygen resulted in the formation of a metabolite tentatively identified as 2-Z-(2'-keto-4'-methylcyclohexylidene)propanal (III; alpha,beta-unsaturated-gamma-keto-aldehyde). The structure assigned was further supported by trapping this metabolite (III) as a cinnoline derivative. Phenobarbital-induced rat liver microsomes also converted 4-methyl-2-cyclohexenone (IV) to 4-hydroxy-4-methyl-2-cyclohexenone (V) and p-cresol (VI) in the presence of NADPH and oxygen. On the basis of both in vivo and in vitro studies, a possible mechanism for the formation of p-cresol from menthofuran has been proposed.     

Metabolic fate of dichlorvos in swine

The metabolic fate of dichlorvos in swine has been studied by short- and long-term oral and inhalation exposure studies utilizing³²P-,³⁶Cl-, or¹⁴C-labeled dichlorvos. In dietary studies slowrelease formulations in PVC were used. No intact dichlorvos could be determined in the blood or tissues of treated animals, and, of the recognized metabolites, only dichloroethanol was found in measurable quantities under some conditions. Studies with³⁶Cl-dichlorvos demonstrated that no organochlorine metabolic residues accumulated in tissues. The cumulative evidence from all studies indicates that the detoxification and degradation of dichlorvos in swine proceeds by essentially the same route whether the compound is administered orally or by inhalation exposure. This degradation proceeds almost exclusively via cleavage of the vinyl-phosphate bond and subsequent dechlorination of the dichlorovinyl product. Evidence is presented for the presence of a symmetrical two-carbon intermediate prior to the formation of glycine, an early metabolic product utilizing the vinyl carbons of the dichlorvos melocule. The isolation and identification of numerous¹⁴C-labeled normal biochemical cell constituents implies that further degradation proceeds via well-recognised metabolic pathways.     

Metabolic fate of mescaline in man

Summary Human subjects given C¹⁴-mescaline by mouth excrete an average of 87% of the dose during the first 24 hours and an average of 92% during the first 48 hours. Average half-life of mescaline in six hours.The composition of the urine in respect to the various metabolites of mescaline from hour to hour has been determined. The concentration of mescaline and its metabolites in the plasma and the cerebrospinal fluid at the various times has also been determined.Mescaline, 3,4,5-trimethoxyphenylacetic acid, N-acetyl--(3,4-dimethoxy-5-hydroxyphenyl) ethylamine and N-acetyl-mescaline have been identified in human urine after mescaline administration in the following amounts: mescaline 55–60%, 3,4,5-trimethoxyphenylacetic acid 27–30%, N-acetyl--(3,4,dimethoxy-5-hydroxyphenyl) ethylamine 5% and N-acetylmescaline less than 0.1%. Five other metabolites have been partially characterized.Chromatographic evidence is presented for the presence of mescaline, 3,4,5-trimethoxyphenylacetic acid, N-acetylmescaline and N-acetyl--(3,4-dimethoxy-5-hydroxyphenyl) ethylamine in the cerebrospinal fluid in man after oral mescaline administration.This investigation was supported in part by Public Health Service Research Grant, MH-10777, from the National Institute of Mental Health.     

Metabolic fate of phenprocoumon in humans

Samples of urine and feces were collected daily from a normal human volunteer who had received a dose of pseudoracemic phenprocoumon [an equimolar mixture of (R)-[12C]- and (S)-[2-13C]phenprocoumon] containing a tracer dose of 10 microCi of [14C]phenprocoumon and analyzed by TLC, HPLC, and GC-MS. After 25 days, 96% of the radiolabeled material was recovered (62.8% in urine and 33.3% in feces). By isotopic dilution and comparison to the Rf values, retention times, and mass fragmentograms of synthetic standards, the metabolites of the drug were identified as the 4'-, 6-, and 7-hydroxy analogues of phenprocoumon. Virtually all of the recovered radioactivity could be accounted for by the parent drug (approximately 40%) and the three metabolites (approximately 60%). The formation of both 4'-(8.1% of administered dose) and 7- (33.4% of administered dose) hydroxyphenprocoumon was highly stereoselective, giving S/R ratios of 2.86 and 1.69, respectively. The formation of 6- (15.5% of administered dose) hydroxyphenprocoumon showed little stereoselectivity (S/R ratio equal to 0.85). The urinary excretion pattern was also confirmed in four additional healthy male subjects who received a single oral dose of pseudoracemic phenprocoumon and whose urine was analyzed by GC-MS. All the drug-related materials (both hydroxylated metabolites and parent compound) that were excreted into the urine were extensively conjugated.     

Metabolic fate of loxistatin in rat

1. The urinary and plasma metabolites of 14C-loxistatin, a new thiol protease inhibitor, were studied after oral administration to rats. 2. The major metabolites in urine were identified as loxistatin acid (M-1), a pharmacologically active form, and its hydroxy metabolites (M-4a and M-4b). These metabolites were also shown to be the major metabolites in plasma. 3. The inhibitory activity of the synthetic metabolite, M-4b, on papain was almost the same as that of loxistatin acid.     

大鼠鼻腔吸收吲哚美辛(英文)

目的,研究吲哚美辛经大鼠鼻腔给药的可行性,方法:用高效液相色谱仪测定血浆中吲哚美辛的药浓变化,比较大鼠吲哚美辛3 mg·kg~(-1)水溶液经口服、静脉与鼻腔给药的吸收特点.结果:鼻腔给药达峰时间为0.08 h,几乎接近于静脉给药;峰浓度为20-O mg·L~(-1),是口服给药的2.4倍.吲哚美辛水溶液鼻腔给药达峰迅速,峰值浓度高,吸收好.结论:低剂量吲哚美辛经鼻腔给药为一合理,可望替代口服的给药方式.