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R Maire-Gauthier T Buronfosse J Magdalou R Herber S Besse P Delatour E Benoit 《Canadian Metallurgical Quarterly》1998,28(6):595-604
1. The stereoselective glucuronidation of carprofen, a non-steroidal anti-inflammatory drug, was investigated in vitro using microsomes prepared from liver of different species (rat, dog, horse, sheep and man) or UGT2B1 expressed in fibroblasts. 2. The Km towards the drug was very similar among these species and for the two enantiomers, whereas the Vmax varied substantially according to the animal used. The rat exhibited a high stereoselective glucuronidation whereas other species, including man, presented a low stereoselectivity. The R-enantiomer was glucuronidated at a more efficient rate than its enantiomorph, and was a better substrate (in terms of Vmax/Km). 3. To explain the enantioselective disposition of carprofen in man and in the different species, the ratio of the enzymatic efficacies (Vmax/Km) were compared with the ratio of the pharmacokinetic parameters AUCs. The basic hypothesis that the intrinsic clearance reflect the enantioselective behaviour of carprofen seemed substantiated when we focused on man and rat glucuronidation, but the in vivo-in-vitro correlation was not possible in other species. 4. In conclusion, the chiral pharmacokinetics of carprofen is less dependent on the stereoselective glucuronidation than other stereoselective processes such as protein binding of carprofen, enzymatic hydrolysis, or renal elimination of glucuronides. 相似文献
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(R)-(+)-Menthofuran is a potent, mechanism-based inactivator of human liver cytochrome P450 (CYP or P450) 2A6. Menthofuran caused a time- and concentration-dependent loss of CYP2A6 activity. The inactivation of CYP2A6 was characterized by a Ki of 2.5 microM and a kinact of 0.22 min-1 for human liver microsomes and a Ki of 0.84 microM and a kinact of 0.25 min-1 for purified expressed CYP2A6. Addition of various nucleophiles, a chelator of iron, or scavengers of reactive oxygen species or extensive dialysis failed to protect CYP2A6 from inactivation. An antibody to metallothionein conjugates of a suspected reactive metabolite of menthofuran was used to detect reactive menthofuran metabolite adducts with CYP2A6. These adducts were formed only in the presence of NADPH-P450 reductase and NADPH. Glutathione, methoxylamine, and semicarbazide did not prevent adduction of reactive menthofuran metabolites to CYP2A6, however. The menthofuran metabolite formation/CYP2A6 inactivation partition ratio was determined to be 3.5 +/- 0.6 nmol/nmol of P450. Menthofuran was unable to inactivate CYP1A2, CYP2D6, CYP2E1, or CYP3A4 in a time- and concentration-dependent manner. 相似文献
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Bremsstrahlung x-rays are produced when energetic beta-particles are emitted and absorbed. Measurements of total-body bremsstrahlung efficiencey (x-ray photon output per muCi 90Sr in the body, relative to that in water) have been made in the intact mouse, rat, rabbit, and dog sacrificed 2 weeks after the injection of 90Sr + 85Sr. Efficiencies were determined by a comparison of the bremsstrahlung output from 90Sr + its daughter 90Y and the gamma-ray emission of 85Sr. Results were checked by a beta-assay of the ashed animals. Bremsstrahlung efficiencies averaged 1.10 in a 0.04 kg mouse, 1.14 in a 0.13 kg rat, 1.23 in a 2.6 kg rabbit, and 1.32 in an 8.5 kg beagle. Extrapolating to a 70 kg human, a relative bremsstrahlung efficiency of about 1.4 is predicted. An estimate was made of the 90Sr body content in a former dial painter based on in vivo counting and a bremsstrahlung efficiency of 1.39 predicted for a 55 kg human female by these animal data. Our value of 1.42 +/- 0.08 muCi 90Sr was in good agreement with corresponding results reported for this subject by 8 other laboratories. 相似文献
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The Wechsler Adult Intelligence Scale (WAIS) was administered to two groups of patients in the Santa Clara County Methadone Maintenance Program who were receiving low and moderate daily stabilized dosages of methadone hydrochloride. In the two separate statistical analyses performed, there were no significant differences found between subtest scores or verbal, performance, and full-scale scores of the groups measured. These results, combined with observations regarding the similarities of WAIS profiles of the two groups, indicate that cognitive functioning as measured by the WAIS was not differentially affected by the two dosages. 相似文献
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The present study was undertaken to evaluate if plasma or CSF beta-endorphin level can be induced to rise during the treatment of heroin addiction by electroacupuncture. Based on the examination of 30 addicts, we obtained no evidence indicating an increase of beta-endorphin level in either the plasma or the CSF after 30 min of acupuncture. In spite of this, the majority of the addicts experienced a reduction of withdrawal symptoms during treatment. Since electroacupuncture may only induce a highly localized secretion of beta-endorphin in the brain, our results cannot unequivocally exclude the possibility that this peptide is involved in mediating the action of acupuncture. 相似文献
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