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81.
AIMS: Formoterol is a beta2-adrenoceptor agonist marketed as a racemic mixture of the active (R; R)- and inactive (S; S)-enantiomers (rac-formoterol). The drug produces prolonged bronchodilation by inhalation but there is significant interpatient variability in duration of effect. Previous work has shown that in humans formoterol is metabolized by conjugation with glucuronic acid but little is known about the stereoselectivity of this reaction. The aim of the present study was to investigate the glucuronidation of formoterol enantiomers in vitro by human liver microsomes. METHODS: The kinetics of formation of formoterol glucuronides during incubation of racemate and of single formoterol enantiomers with human liver microsomes (n=9) was characterized by chiral h.p.l.c. assay. RESULTS: The kinetics of glucuronidation of the two formoterol enantiomers obeyed the Michaelis-Menten equation. Glucuronidation of formoterol was stereoselective and occurred more than two times faster for (S; S)-formoterol than for (R; R)-formoterol. In incubations with single formoterol enantiomers, the median (n=9) Km values for (R; R)-glucuronide and (S; S)-glucuronide were 827.6 and 840.4 microm, respectively, and the median V max values were 2625 and 4304 pmol min-1 mg-1, respectively. Corresponding values determined in incubations with rac-formoterol were 357.2 and 312.1 microm and 1435 and 2086 pmol min-1 mg-1 for (R; R)- and (S; S)-glucuronide, respectively. Interindividual variation was large with the ratio of V max/Km (S; S/R; R) ranging from 0.57 to 6.90 for incubations with rac-formoterol. CONCLUSIONS: Our study demonstrates that glucuronidation of formoterol by human liver microsomes is stereoselective and subject to high interindividual variability. These findings suggest that clearance of formoterol in humans is subject to variable stereoselectivity which could explain the variation in duration of bronchodilation produced by inhaled formoterol in patients with asthma. 相似文献
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Heart failure in congenital thyrotoxicosis 总被引:1,自引:0,他引:1
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Indium-111 chloride imaging in chronic osteomyelitis 总被引:1,自引:0,他引:1
Sixty-eight patients with clinically suspected chronic osteomyelitis were studied with [111In]chloride. Fifty-four images were categorized as true positive; seven were categorized as true negative. There were four false-positive studies, two of which were associated with healing cancellous bone grafts. There were three false-negative studies in patients previously treated with long-term antibiotic therapy. Images in eight noninfected healing fractures 3 to 8 mo old were normal. Three patients with infected total hip prostheses had positive images. Two patients with loose prostheses had negative images. This study shows that [111In]chloride imaging is an accurate way to localize chronic osteomyelitis and may overcome some of the disadvantages of [67Ga]citrate such as localization in noninfected healing fractures and in some loose [67Ga]citrate such as localization in noninfected healing fractures and in some loose prostheses. 相似文献
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