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At least 19 recordsLinked to original sources
PubMed1989

Studies on the mechanism of coumarin-induced toxicity in rat hepatocytes: comparison with dihydrocoumarin and other coumarin metabolites.

Single doses of coumarin (125 mg/kg, ip) produced a depletion of hepatic nonprotein sulfhydryl groups (mainly reduced glutathione; GSH) in young male Sprague-Dawley rats after 2 hr and increased liver weight and produced hepatic centrilobular necrosis after 24 hr. Coumarin also produced time- and dose-dependent toxic effects in primary rat hepatocyte cultures. A marked reduction of GSH levels was also observed in vitro and this was not due either to the formation of oxidized glutathione (GSSG) or to the leakage of GSH and/or GSSG from the hepatocytes. Coumarin-induced toxicity in rat hepatocytes could be inhibited by the cytochrome P450 inhibitors ellipticine and metyrapone and potentiated by depleting hepatocyte GSH levels with diethyl maleate. In contrast to coumarin, dihydrocoumarin--which lacks the 3,4-double bond--produced little toxicity in rat hepatocytes either in vivo (127 and 254 mg/kg, ip) or in vitro. Similarly, coumarin was more toxic to rat hepatocytes than a number of known coumarin metabolites including 3- and 7-hydroxycoumarin and o-hydroxyphenylacetic acid. The results of these studies demonstrate a good in vivo/in vitro correlation for the effects of coumarin and dihydrocoumarin in rat hepatocytes. Furthermore, the data suggest that coumarin hepatoxicity in the rat is due to coumarin bioactivation by cytochrome P450-dependent enzymes to a toxic metabolite(s), which may be a coumarin 3,4-epoxide intermediate. GSH appears to protect against coumarin-induced toxicity possibly by the formation of conjugates with the toxic coumarin metabolite(s).

Animals↗
PubMed1994

Studies on the acute effects of coumarin and some coumarin derivatives in the rat.

The mechanism of acute coumarin-induced hepatotoxicity in the rat has been investigated by comparing the effects of coumarin with those of a number of methyl-substituted coumarin derivatives. Male Sprague-Dawley rats were given single ip doses of corn oil (control), coumarin (0.86 and 1.71 mmol/kg body weight), 3,4-dimethylcoumarin (3,4-DMC, 1.71 and 2.57 mmol/kg), 3-, 4- and 6-methylcoumarins (3-MC, 4-MC and 6-MC, 1.71 mmol/kg) and 3- and 4-methyloctahydrocoumarins (3-MOHC and 4-MOHC, 2.57 mmol/kg) and hepatotoxicity assessed after 24 hr. Coumarin administration produced dose-related hepatic necrosis and a marked elevation of plasma alanine aminotransferase and aspartate aminotransferase activities. In contrast, none of the coumarin derivatives examined produced either hepatic necrosis or elevated plasma transaminase activities. Treatment with coumarin reduced hepatic microsomal ethylmorphine N-demethylase and 7-ethoxycoumarin O-deethylase activities, whereas one or both mixed-function oxidases appeared to be induced by treatment with 3,4-DMC, 4-MC, 3-MOHC and 4-MOHC. These results provide further evidence that acute coumarin-induced hepatotoxicity in the rat is due to the formation of a coumarin 3,4-epoxide intermediate. That 3- and/or 4-methyl substitution (i.e. 3-MC, 4-MC and 3,4-DMC) leads to a reduction in coumarin-induced hepatotoxicity, due to diminished formation of 3,4-epoxide intermediates, was confirmed by the results of molecular orbital calculations.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1981

Pilot study on bioavailability of coumarin and 7-hydroxycoumarin upon peroral administration of coumarin in a sustained-release dosage form.

Prolonged-release tablets containing coumarin were compared to intravenous and peroral administration of coumarin solution in man. Unchanged coumarin, the Phase 1 metabolite 7-hydroxycoumarin, and the Phase II metabolite 7-hydroxycoumarin glucuronide were determined in whole blood. Upon peroral administration, only approximately 1 per cent coumarin was found unchanged in the systemic circulation. However, the amount of the glucuronide found indicates complete absorption with extensive first-pass effect. When the prolonged-release dosage form was compared to the peroral solution, the extent of bioavailability of coumarin was 35 per cent, whereas the 7-hydroxycoumarin glucuronide was totally available. This supports the hypothesis that coumarin might be a prodrug and 7-hydroxycoumarin the active moiety. The drug liberation of coumarin from the sustained-release tablets follows first-order kinetics. A linear correlation was found between per-cent of drug released in vitro and the area under the concentration-time curve, AUC (O-t), of total 7-hydroxycoumarin (7HC + 7HCG).

Biological Availability↗
PubMed1977

Pharmacokinetics of coumarin and its 7-hydroxy-metabolites upon intravenous and peroral administration of coumarin in man.

The pharmacokinetics of coumarin (C) upon i.v. and p.o. administration and its metabolites 7-hydroxy-coumarin (7-HC) and 7-hydroxy-coumarin glucuronide (7-HCG) have been studied. Six healthy volunteers were involved in this investigation. Four of the volunteers participated in a crossover study. Coumarin was administered i.v. and p.o. in dose sizes of 0.25 mg/kg and 0.857 mg/kg, respectively. Coumarin is rapidly absorbed p.o., however the availability to systemic circulation is less than 4%. The rest of the dose appears quantitatively as 7-HC and 7-HCG in systemic circulation suggesting an extensive firstpass effect. Coumarin and 7-HCG are best fitted to an open two-compartment model, whereas 7-HC is best fitted to an open one-compartment model. The biological half-life of both C (0.80 vs. 1.02 h) and 7-HCG (1.47 vs. 1.15 h) was not significantly different for the two routes of administration. The large total clearance of C again suggests a first-pass effect; while that of 7-HCG, which is nearly exclusively eliminated into urine, indicates active tubular secretion of the glucuronide.

Administration, Oral↗
PubMedDate not supplied

Coumarin mercapturic acid isolated from rat urine indicates metabolic formation of coumarin 3,4-epoxide.

A coumarin mercapturic acid, N-acetyl-S-(3-coumarinyl)cysteine, has been identified in the urine of coumarin-treated rats. [14C]Coumarin was applied by gavage as a single dose to male Wistar rats (10-150 mg/kg body weight). Twenty-four-hour urine was collected, and the deproteinized concentrate was analyzed for radiolabeled metabolites by HPLC. The new mercapturic acid metabolite is supposed to result from oxidative biotransformation of coumarin to its 3,4-epoxide and subsequent coupling with glutathione.

Acetylcysteine↗
PubMed1994

Structures of new coumarins and antitumor-promoting activity of coumarins from Angelica edulis.

From the fruits of Angelica edulis Miyabe (Umbelliferae), three new angular furanocoumarins, edulisin III (1), edulisin IV (2), and edulisin V (3), were isolated along with three known coumarins, 2'(S), 3'(R)-3'-isobutyryloxy-4'-acetoxy-2',3'-dihydrooroselol (4), edultin (5), and 2'(S),3'(R)-3'-senecioyloxy-4'-acetoxy-2',3'-dihydrooroselol (6), respectively. The structures of 1 and 2 were established to be 2'(S),3'(R)-3'-(2-methylbutyryloxy)-4'-acetoxy-2',3'-dihydrooro selol and 2'-(S),3'(R)-3'-propyryloxy-4'-acetoxy-2',3'-dihydrooroselol by chemical studies and spectral analyses. Coumarin 3 was proved to be 3'-(2-methylbutyryl-oxy)-4'-angeloyloxy-2',3'-dihydrooroselol++ + by chemical and spectral analyses and H-C COLOC. Coumarins 1-6 were examined for the effects on tumor-promotor induced phenomena in vitro. Among these coumarins, 3 showed the most potent inhibitory activity on 12-O-tetradecanoylphorbol 13-acetate (TPA)-stimulated 32Pi incorporation into phospholipids of cultured cells.

Antineoplastic Agents, Phytogenic↗
PubMed1983

Pharmacokinetics of coumarin, 7-hydroxycoumarin and 7-hydroxycoumarin glucuronide in the blood and brain of gerbils following intraperitoneal administration of coumarin.

Blood and brain concentration-time profiles were obtained in gerbils following intraperitoneal administration of coumarin (C). The data were fit to one- or two-compartment models using several computer programs including NONLIN, modified ESTRIP, RESID and AUC-RPP. The data indicate that coumarin distributes rapidly into the brain tissue reaching about one half the blood concentration at peak time. The peak time brain coumarin concentration and subsequent rapid removal from brain correlates well with the transient sedative effect of coumarin. Area under the curve estimations indicate that 7-hydroxycoumarin and 7-hydroxycoumarin glucuronide distribute into brain tissue to a negligible extent if at all. The pharmacokinetic profile of C as well as the metabolic 7-hydroxylation and glucuronidation found in the blood of the gerbil is similar to that found in man. This would suggest that the gerbil is potentially a good model for pharmacokinetic and pharmacological investigations of C for correlation with human studies.

Animals↗
PubMed1975

Effect of coumarin and some coumarin derivatives on active transport and passive diffusion of sugars by chicken and rat intestine, in vitro.

The effect of coumarin, 4-hydroxycoumarin, coumarin-3-carboxylic acid and acenocoumarol on the active transport of D-galactose and the passive diffusion of arabinose by intestinal sacs was studied. All these substances, when added to the mucosal medium of incubation at concentrations from 10(-4) to 10(-3) M, inhibit the active transport of D-galactose and increase the diffusion of arabinose. Oxygen uptake by the intestinal tissue is only inhibited by coumarin-3-carboxylic acid. The results suggest that the effects obtained are probably due to an alteration in intestinal permeability, to inhibition of cell metabolism and to molecular size.

Acenocoumarol↗
PubMed1978

Histological and histochemical investigations of the epiphyseal cartilage in rats after administration of heparin, coumarin as well as coumarin and diphosphonate (EHDP).

Heparin and coumarin (Marcumar) as well as coumarin combined with a diphosphonate (EHDP) were examined histologically and histochemically with regard to their effect on the structure of the epiphyseal cartilage in rats. Topo-optical reactions were used to assess the submicroscopic structural changes in the developing trabeculae of metaphysis. The zone of resting cartilage and the zone of young proliferation cartilage in epiphyseal plates revealed a reduced cell count due to the influence of anticoagulants. With regard to the matrix of the epiphyseal plate, it may be stated that its ultrastructure appeared partly regular and that, on the other hand, large areas of degeneration were detected in the connective-tissue. The negative effect of anticoagulants on the ground substance could not be reduced definitely by means of a diphosphonate (EHDP) in conjunction with Marcumar which was administered simultaneously.

Animals↗
PubMed1991

[Studies on the chemical constituents of rutaceous plants. LXVII. The chemical constituents of Toddalia asiatica (L.) Lam. (T. aculeata Pers). Examination of coumarins using supercritical fluid and soxhlet extraction. Is toddalolactone a genuine natural coumarin?].

It is well known that toddalolactone (1) is a main component of Toddalia asiatica (L.) Lam. (T. aculeata Pers.) (Rutaceae). However, supercritical fluid (SCF) extraction of the plant by using CO2 showed that a main component of the extract was not 1, but aculeatin (2), a coumarin having an epoxy ring on the side chain. The same result was obtained from Soxhlet extraction by using aprotic solvents. On the other hand, Soxhlet extraction by using methanol yielded 13, corresponding to a methanol adduct of 2, as an additional component, which was able to be also produced in 50.2% yield only by heating pure 2 in methanol, indicating that the epoxy ring in 2 can be easily attacked by a weak nucleophile like methanol. These facts strongly suggested that 1, corresponding to the hydrate of 2, was an artefact derived from 2 during extraction. SCF extraction under various conditions was examined in detail by quantitative analyses of 1 and 2 by high performance liquid chromatography and the optimum condition extracting the both components was found to be at 40 degrees C and at 300 kg/cm2. The condition was applied to the plant treated with aqueous sodium hydrogen carbonate in order to remove any acidic substances and 1 was still detected in the extract. Thus, it is conclude that 1 should be a genuine natural coumarin but that previous isolation of 1 as a main component resulted in an isolation of an artefact derived from 2. SCF extraction was suggested to be a useful extraction method.

Chemical Fractionation↗
PubMed1983

Dose-related pharmacokinetics of coumarin, 7-hydroxycoumarin and 7-hydroxycoumarin glucuronide upon intraperitoneal administration of coumarin and 7-hydroxycoumarin in the rat.

Blood concentration-time data of coumarin (C), 7-hydroxycoumarin (7-HC) and 7-hydroxycoumarin glucuronide (7-HCG) were obtained in rats receiving intraperitoneal doses of C ranging from 2.5 to 60 mg/kg and of 7-HC ranging from 2.5 to 20 mg/kg. Coumarin blood levels were fit to pharmacokinetic models using computer programs including NONLIN, modified ESTRIP, RESID and AUCRPP. The other molecular species were treated pharmacokinetically by linear least squares regression analysis. C blood concentrations were indicated to be dose-dependent at doses greater than 10 mg/kg. Only trace amounts of 7-HC were found upon C administration, however, 7-HCG was found in measurable quantities at all dose levels. The blood concentration-time data of 7-HC and 7-HCG were very erratic with considerable intersubject variation. 7-HC levels upon 7-HC dosing were found to have extremely short half-lives of elimination for all animals tested. Deviation from linearity was apparent at the 20 mg/kg dose for 7-HC. The 7-HCG metabolite upon 7-HC dosing also showed dose-dependent kinetics at the 20 mg/kg dose. 7-HCG was found to appear at variable rates in the blood with peak times ranging from about 2 to 50 min.

Animals↗