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31.
Alexander Sparreboom Manon T. Huizing Jan J. B. Boesen Willem J. Nooijen Olaf van Tellingen Jos H. Beijnen 《Cancer chemotherapy and pharmacology》1995,36(4):299-304
Three metabolites of the cytotoxic drug paclitaxel (Taxol) were isolated and purified from the feces of cancer patients receiving the agent as an intravenous infusion. The procedures involved sample homogenization in water followed by liquid-liquid extraction with diethyl ether and high-performance liquid chromatography (HPLC). Approximately 1–3.5 mg of each metabolite was obtained from 100 g of feces. As judged from the chromatographic traces of analytical HPLC with ultraviolet (UV) detection at 227 nm, the purity of each compound was >97%. On-line photodiode-array detection demonstrated that the UV spectrum of the isolated compounds closely resembles that of the parent drug. Mass spectrometry provided evidence that these metabolites are mono- and dihydroxy-substituted derivatives, namely, 6-hydroxypaclitaxel, 3-p-hydroxypaclitaxel, and 6,3-p-dihydroxypaclitaxel. The two 6-hydroxy-substituted metabolites were shown to have lost their cytotoxicity in in vitro clonogenic assays using the A2780 human ovarian carcinoma and the CC531 rat colon-carcinoma tumor cell lines. In addition, the metabolites showed reduced myelotoxic effects as compared with paclitaxel in an in vitro hemopoietic progenitor toxicity assay. Our procedure for the isolation and purification of paclitaxel metabolites in milligram quantities should be useful for testing the biological activities of these compounds and for the preparation of calibration standards essential for pharmockinetics studies. 相似文献
32.
Danny D. Shen James P. Hosler Richard L. Schroder Daniel L. Azarnoff 《Journal of pharmacokinetics and pharmacodynamics》1980,8(1):53-68
The pharmacokinetics of hydralazine (H) and its acid-labile hydrazone metabolites were compared in rapid and slow acetylators. Following a 20-mg intravenous infusion, the elimination half-life (t1/2) and the apparent volume of distribution of H did not differ between the two groups. Plasma clearance estimates approached hepatic blood flow. When a single 100-mg dose of H was given-orally, the area under the plasma concentration-time curve (AUC) and systemic availability () in slow acetylators were, on the average, twice as high as in the rapid acetylators, indicating a difference in the extent of first-pass metabolism of the drug. Furthermore, the observed in the slow individuals exceeded theoretical predictions. Hence saturation of first-pass metabolism of H is suggested, and a nonlinear relationship between AUC and oral dose of H was indeed observed in the three subjects studied with two doses. The half-life of decline of the acidlabile metabolites was similar to the t1/2 of H. The AUCs for metabolites were 4–12 times larger than for the parentdrug. However, the ratio between the metabolite AUC and drug AUC did not differ irrespective ofroutes of administration or the acetylator status.This study was supported in part by Grant RR 828 from United States Public Health Service and a Research Starter grant from the Pharmaceutical Manufacturers Association Foundation, Inc. (D. D. S.). 相似文献
33.
In a drug discrimination paradigm pigeons and rats were trained with an operant procedure to discriminate between the presence and absence of the effects of 9-THC (1.0 and 3.0 mg/kg, injected IM 90 min and I.P. 30 min before the start of the session). Once trained, various THC metabolites as well as a water-soluble derivative of THC (SP-111), were substituted for 9-THC to test for generalization to the training drug. Generalization to 9-THC occurred with the 11-hydroxy metabolites and the potency order was 11-OH-9-THC >11-OH-8-THC 9-THC. Among the other metabolites tested (8-OH-9-THC, 8, 11-di-OH-9-THC, 8-OH-9-THC, 8, 11-di-OH-9-THC), it was only 11-di-OH-9-THC that completely substituted for 9-THC in pigeons, albeit at very high dose levels (rats were not tested with these metabolites). SP-111 generalized to 9-THC in both species. However, the onset of action of SP-111 was slower than that for 9-THC, especially in pigeons. These studies show the importance of obtaining complete dose-effect determinations over time when assessing structure-activity relationships with drug-discrimination procedures.A brief account of the results, which are summarized in Neuropharmacology 18:1023–1024, 1979), was presented at the British Association for Psychopharmacology Summer Conference, July 15–17, Birmingham, England, 1979 相似文献
34.
L. Perbellini F. Brugnone R. Silvestri E. Gaffuri 《International archives of occupational and environmental health》1981,48(1):99-106
Summary A gas chromatographic method for analyzing the urinary metabolites of n-hexane (2-hexanol, 2,5-hexanedione, 2,5-dimethylfuran and -valerolactone), of 2-methylpentane (2-methyl-2-pentanol), of 3-methylpentane (3-methyl-2-pentanol), and of cyclohexane (cyclohexanol) was developed. Processing of urine and the gas chromatographic conditions are described. The recovery rate of all hexane metabolites, except 2,5-dimethylfuran, ranged between 92 and 100%. The variation coefficient of metabolites determination was between 1.5 and 5%, apart from 2,5-dimethylfuran determination for which the variation coefficient was 15%. The detection limits ranged between 0.2 and 0.7 mg/1 and between 0.05 and 0.1 mg/1 when a packed or capillary column was used. Results obtained from a packed and capillary column are discussed. 相似文献
35.
M. R. Dobrinska D. E. Furst T. Spiegel W. C. Vincek R. Tompkins D. E. Duggan R. O. Davies H. E. Paulus 《Biopharmaceutics & drug disposition》1983,4(4):347-358
The biliary secretion of sulindac and metabolites after a single 400 mg oral dose of the drug was studied in 3 elective gallbladder surgical patients following placement of an occludable T-tube in the common bile duct. Bile and systemic plasma were sampled at frequent intervals for up to 36 h postdose. The apparent biliary clearance (V?cl,bilc) of the prodrug sulindac is about 25 times greater than that of the pharmacologically active sulfide metabolite. The total biliary flux of drug in normal man with an uninterrupted enterohepatic cycle, calculated from V?cl,bile and historic mean plasma drug AUC values, averages 144 and 12·2 per cent of the dose as sulindac and the sulfide metabolite, respectively. Thus, enterohepatic recycling of the drug in man is principally in the form of the prodrug which not only limits exposure of the intestine to the active moiety but also sustains systemic concentrations of active drug upon reabsorption of the prodrug. 相似文献
36.
Determination of tetrahydrophtalimide and 2-thiothiazolidine-4-carboxylic acid,urinary metabolites of the fungicide captan,in rats and humans 总被引:1,自引:0,他引:1
R. T. H. van Welie P. van Duyn E. K. Lamme P. Jager B. L. M. van Baar N. P. E. Vermeulen 《International archives of occupational and environmental health》1991,63(3):181-186
Summary Capillary gas chromatographic (GC) methods using sulphur and mass selective detection for the qualitative and quantitative determination of tetrahydrophtalimide (THPI) and 2-thiothiazolidine-4-carboxylic acid (TTCA), urinary metabolites of the fungicide captan in rat and humans, were developed. Urinary detection limits were 2.7 g/l for THPI and 110 g/l for TTCA. Intraperitoneal and oral administration of captan to rats resulted in a 48-h cumulative urinary excretion of THPI of 1%–2% and 3%–9% of the dose, respectively. Cumulative urinary excretion of TTCA over 48 h ranged from 2% to 5% of the captan dose for the respective routes of administration. In urine of non-exposed human subjects, neither THPI nor TTCA could be detected. In urine of fruit-growers who were occupationally exposed to captan, both THPI and TTCA could be detected. Based on these results, THPI and TTCA are proposed as promising parameters for the biological monitoring of occupational exposure to captan. 相似文献
37.
A. Anadón M. R. Martinez-Larrañaga M. J. Díaz P. Bringas M. C. Fernandez 《Archives of toxicology》1991,65(2):156-159
The effect of deltamethrin pretreatment on the pharmacokinetics and metabolism of antipyrine was studied in male rats. The total plasma clearance of antipyrine was significantly decreased by deltamethrin pretreatment (20 mg/kg and 40 mg/kg daily for 6 days prior to antipyrine administration), while the elimination half-life at phase, the area under the concentration-time curve and the mean residence time of antipyrine were significantly increased. The magnitude of the observed changes was dose dependent. The urinary excretion of norantipyrine, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine was decreased by 39%, 32% and 26%, respectively (p<0.001) in the presence of deltamethrin. In addition, the rate constants for formation of each of these metabolites were significantly decreased by an average of approximately 71%. These results suggest that deltamethrin is capable of inhibiting oxidative metabolism, a finding which could be of clinical and toxicological significance. 相似文献
38.
H. Fuder R. Siebenborn E. Muscholl 《Naunyn-Schmiedeberg's archives of pharmacology》1982,318(4):301-307
Summary Isolated rat hearts with the right sympathetic nerves attached were perfused at a constant flow rate of 7 ml/min with Tyrode's solution. (-)-3H-Noradrenaline (final concentration 10–13.9 nM) was infused for 10 min to label the noradrenaline stores. After wash-out the sympathetic nerves were stimulated electrically (3 Hz, 180 impulses, 1 ms, 20–30 mA) three times (S1–S3) at intervals of 15 min. 3H-Noradrenaline and its metabolites were determined by liquid scintillation counting according to Graefe et al. (1973).Both, nicotine 50 M and p-aminophenethyltrimethylammonium (PAPETA) 30 M, enhanced the 3H-noradrenaline overflow in the absence of nerve stimulation. The effect of PAPETA was biphasic and was still observed in the presence of N-methylatropine 0.1 M. Hexamethonium 10 M abolished the first phase only, but cocaine 10 M antagonized both phases.The decline of the stimulation-evoked overflow of 3H-noradrenaline from the first to the third stimulation period was similar in the absence and in the presence of cocaine 10 M starting before S1 and perfused throughout. Cocaine 10 M added before S2, however, enhanced the evoked overflow by 77%.PAPETA 30 M increased the stimulation-evoked overflow by 67% in the absence, and by 73% of the respective control in the presence, of hexamethonium 10 M. PAPETA 30 M failed to enhance the evoked overflow in the presence of cocaine. Hexamethonium (added before S2) did not modify the effectiveness of nerve stimulation.Nicotine, neither when perfused from 6 min before S2, nor when added to the perfusion fluid simultaneously with the onset of nerve stimulation, caused changes in the 3H-noradrenaline output upon S2.Upon stimulation a rather discrete increase in 3H-DOPEG overflow was observed. This increase was abolished by cocaine and/or PAPETA.It is concluded that nicotine and PAPETA stimulate the output of 3H-noradrenaline from the rat heart sympathetic nerves by activation of nicotine receptors. However, the amount of transmitter released is small. Neither drug appeared to modulate the output of 3H-noradrenaline upon electrical nerve stimulation via nicotine receptors.PAPETA, like cocaine, appears to block the reuptake of released transmittsrs thereby enhancing the 3H-noradrenaline overflow and reducing the overflow of 3H-DOPEG (formed intraneuronally from recaptured noradrenaline after nerve stimulation).Abbreviations used DOMA
3,4-dihydroxymandelic acid
- DOPEG
3,4-dihydroxyphenylglycol
- MOPEG
3-methoxy-4-hydroxy-phenylglycol
- NA
noradrenaline
- NMN
normetanephrine
- OMDA
O-methylated deaminated metabolites (sum of MOPEG and VMA)
- PAPETA
p-aminophenethyltrimethylammonium
- VMA
3-methoxy-4-hydroxymandelic acid 相似文献
39.
Summary The blood chemistry and clinical pharmacokinetics of thioridazine and its metabolites, side-chain sulphoxide, side-chain sulphone and ring sulphoxide, were studied in 31 alcoholics and were compared with values in 17 thioridazine-treated controls without alcoholism. Pathological blood chemistry values, including abnormal liver function and protein concentrations, were common among the alcoholics. In relation to dosage, the majority had a low serum concentration of thioridazine and at a given concentration of thioridazine they had high serum concentrations of its metabolites. Positive intercorrelations were found between pathological liver function tests, prolonged serum half-life and increased serum concentration of thioridazine. The free fractions of thioridazine, side-chain sulphoxide and ring sulphoxide were significantly higher and those of the side-chain sulphone lower in the alcoholics than in the controls. The free fractions of side-chain and ring sulphoxide were significantly increased in patients with a low concentration of 1-acid glycoprotein. 相似文献
40.
When rats were dosed with 14 g/kg 3H-isoproterenol, 3H-radioactivity was measurable in the liver until 48 h. This amount was not different in livers of animals which have been pretreated with diethyl maleate.After exhaustive extraction, a significant amount of 3H-radioactivity from isoproterenol could be detected in the proteins of total liver (homogenate), of cytosol and of microsomes. In the cytosol fraction of diethyl maleate pretreated animals twice the amount of isoproterenol-radioactivity was found in the extracted proteins compared to controls. In the microsomal fraction there was no difference between diethyl maleate pretreated and control animals in the amount of radioactivity incorporated into proteins.In all fractions the radioactivity measurable in the extracted proteins declined with a half life time of about 24 h.The in vivo results on covalent binding of isoproterenol are compared to the irreversible protein binding of ethinyloestradiol in vivo. Quantitatively, these in vivo data are compared to the results on irreversible protein binding obtained during incubations of isoproterenol or ethinyloestradiol with rat liver microsomes.Presented at the Symposium Influence of Metabolic Activations and Inactivations on Toxic Effects held at the 18th Spring Meeting of the Deutsche Pharmakologische Gesellschaft, Section Toxicology, D-6500 Mainz, March 15, 1977 相似文献