Stereoselective glucuronidation of formoterol by human liver microsomes

Zhang, Mei; Fawcett, J. Paul; Kennedy, Julia; Shaw, John

doi:10.1046/j.1365-2125.2000.00133.x

Cited by 26 publications

(16 citation statements)

References 20 publications

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“…In this study, we investigated the glucuronidation activity of etodolac, diclofenac, and ibuprofen metabolized by UGTs. Because glucuronidations of a chiral compound can be enantioselective like the several other chiral drugs reported (Silber et al, 1982;Zhang et al, 2000), there are enantiomerenantiomer interactions between one enantiomer and the other (el Mouelhi et al, 1987). In this study, kinetic parameters of S-ibuprofen, R-ibuprofen, and rac-ibuprofen were similar in microsomes of humans, hUGT1 mice, and regular mice (Table 2).…”

Section: Discussionmentioning

confidence: 99%

Glucuronidation of Drugs and Drug-Induced Toxicity in HumanizedUDP-Glucuronosyltransferase 1Mice

et al. 2014

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UDP-glucuronosyltransferases (UGTs) are phase II drug-metabolizing enzymes that catalyze glucuronidation of various drugs. Although experimental rodents are used in preclinical studies to predict glucuronidation and toxicity of drugs in humans, species differences in glucuronidation and drug-induced toxicity have been reported. Humanized UGT1 mice in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus (hUGT1 mice) were recently developed. In this study, acyl-glucuronidations of etodolac, diclofenac, and ibuprofen in liver microsomes of hUGT1 mice were examined and compared with those of humans and regular mice. The kinetics of etodolac, diclofenac, and ibuprofen acyl-glucuronidation in hUGT1 mice were almost comparable to those in humans, rather than in mice. We further investigated the hepatotoxicity of ibuprofen in hUGT1 mice and regular mice by measuring serum alanine amino transferase (ALT) levels. Because ALT levels were increased at 6 hours after dosing in hUGT1 mice and at 24 hours after dosing in regular mice, the onset pattern of ibuprofen-induced liver toxicity in hUGT1 mice was different from that in regular mice. These data suggest that hUGT1 mice can be valuable tools for understanding glucuronidations of drugs and druginduced toxicity in humans.

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Section: Discussionmentioning

confidence: 99%

Glucuronidation of Drugs and Drug-Induced Toxicity in HumanizedUDP-Glucuronosyltransferase 1Mice

et al. 2014

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“…The glucuronidation of formoterol occurs mainly at the phenolic position, but a benzyl glucuronide is also formed [5]. Glucuronidation has also been studied using human liver microsomes and chiral assay has shown it to be stereoselective with large interindividual variation [6].…”

Section: Introductionmentioning

confidence: 99%

Stereoselective urinary excretion of formoterol and its glucuronide conjugate in human

Mei

Fawcett

Shaw

2002

Brit J Clinical Pharma

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Aims Formoterol is an inhaled β 2 -adrenoceptor agonist used as a racemic mixture of the active (R; R)-and inactive (S; S)-enantiomers ( rac -formoterol). Glucuronidation is an important route of metabolism in humans which occurs faster for (S; S)-formoterol in human liver microsomes. The aim of this study was to investigate the stereoselectivity of urinary excretion of formoterol and its glucuronide conjugate after oral dosing with rac -formoterol. Methods Seven nonsmoking volunteers (six males, one female) were included in the study. After an overnight fast, a single 60 µ g oral dose of rac -formoterol fumarate dihydrate was ingested. Urine samples were collected at 1 h intervals for the first 4 h, and at 6, 8, 12 and 24 h after dosing. Formoterol enantiomers were analysed by chiral h.p.l.c. assay and formoterol glucuronides were determined as formoterol enantiomers after enzymatic cleavage with β -glucuronidase. Results The female subject displayed a different pattern of metabolism and statistical analysis was therefore limited to data for the six males. The median (range) of the total urinary excretion of formoterol was 37.8% (20.9-51.2%) of the dose. The medians (ranges) of the amounts of (R; R)-and (S; S)-formoterol and of (R; R)-and (S; S)-formoterol glucuronide excreted were 2.1 (1.0-2.9), 3.5 (2.6-3.8), 21.0 (13.1-31.0) and 10.3 (4.2-14.6)%, respectively, of the dose. Unchanged (S; S)-formoterol excretion was significantly greater than that of unchanged (R; R)-formoterol and (R; R)-formoterol glucuronide excretion was significantly greater than that of (S; S)-formoterol glucuronide. The total RR-formoterol (unchanged drug plus glucuronide) excreted was significantly greater than the total (S; S)-formoterol. Conclusions Our study demonstrates that the urinary excretion of formoterol in male humans after oral administration of rac -formoterol is stereoselective with preferential excretion of the active (R; R)-formoterol as unchanged drug and glucuronide. The different pattern of metabolism in the female subject provides impetus for further studies of the effect of gender on the stereoselective metabolism and pharmacokinetics of formoterol.

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“…Moreover, pharmacokinetic studies have found that the metabolic clearance of S-salbutamol occurs at a significantly lower rate than that of R-salbutamol, such that the unwanted effects may persist after the beneficial actions have worn off [161]. Evidence is available that S,Sformoterol (inactive) may also accumulate in vivo relative to the active R,R-stereoisomer due to differential rates of metabolism [162]. In view of these data, it is perhaps not surprising that many new long-acting b 2 -adrenoceptor agonists in clinical development are pure pharmacologically active enantiomers [142].…”

Section: Racemic Formulationsmentioning

confidence: 99%

Beyond the dogma: novel 2-adrenoceptor signalling in the airways

Giembycz

Newton²

2006

European Respiratory Journal

132

118

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b 2 -Adrenoceptor agonists evoke rapid bronchodilatation and are the mainstay of the treatment of asthma symptoms worldwide. The mechanism of action of this class of compounds is believed to involve the stimulation of adenylyl cyclase and subsequent activation of the cyclic adenosine monosphosphate (cAMP)/cAMP-dependent protein kinase cascade.This classical model of b 2 -adrenoceptor-mediated signal transduction is deeply entrenched, but there is compelling evidence that agonism of b 2 -adrenoceptors can lead to the activation of multiple effector pathways, which now compels researchers in academia and the pharmaceutical industry alike to think beyond the traditional dogma. Therefore, the regulation by b 2 -adrenoceptor agonists of responses, including airways smooth muscle tone and the secretory capacity of the epithelium and pro-inflammatory/immune cells, may be highly complex, involving both cAMPdependent and -independent mechanisms that, in many cases, may act in concert.In this article, the current status of b 2 -adrenoceptor-mediated signalling in the airways is reviewed in the context of understanding mechanisms that may underlie both the beneficial and detrimental effects of these drugs in asthma symptom management.

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Stereoselective glucuronidation of formoterol by human liver microsomes

Cited by 26 publications

References 20 publications

Glucuronidation of Drugs and Drug-Induced Toxicity in HumanizedUDP-Glucuronosyltransferase 1Mice

Glucuronidation of Drugs and Drug-Induced Toxicity in HumanizedUDP-Glucuronosyltransferase 1Mice

Stereoselective urinary excretion of formoterol and its glucuronide conjugate in human

Beyond the dogma: novel 2-adrenoceptor signalling in the airways

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