Glucuronidation of the Enantiomers of E‐10‐Hydroxynortriptyline in Human and Rat Liver Microsomes

Dumont, Étienne; Perry, Thomas L.

doi:10.1111/j.1600-0773.1987.tb01831.x

Cited by 16 publications

(11 citation statements)

References 29 publications

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“…The interindividual variation in uridine 5′‐diphospho‐ glucuronosyltransferase (UDPGT) activity may be related to differences in age, sex, diet, disease state, exposure to xenobiotics or pharmacogenetics [20, 21]. In addition, it has been shown that some human UDPGT isoenzymes are stereoselective [22, 23] and that some can be selectively induced by pretreatment with different agents [21, 24]. Since most of the liver samples in our study were surgical waste from patients undergoing removal of liver tumours, the large variation in UDPGT activity and stereoselectivity is more likely to reflect the influence of disease state and/or previous drug treatment.…”

Section: Discussionmentioning

confidence: 99%

Stereoselective glucuronidation of formoterol by human liver microsomes

Zhang

Fawcett

Kennedy

et al. 2000

Brit J Clinical Pharma

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Aims Formoterol is a b 2 -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) K m values for (R; R)-glucuronide and (S; S)-glucuronide were 827.6 and 840.4 mm, respectively, and the median V max values were 2625 and 4304 pmol min Interindividual variation was large with the ratio of V max /K m (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.

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Section: Discussionmentioning

confidence: 99%

Stereoselective glucuronidation of formoterol by human liver microsomes

Zhang

Fawcett

Kennedy

et al. 2000

Brit J Clinical Pharma

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“…The major metabolite of nortriptyline is E-10-hydroxynortriptyline, which is further glucuronidated (Dumont et al 1987) at the 10-hydroxy group. Similar studies with morphine as inhibitor and nortriptyline or amitriptyline as substrates of the UDPGT have revealed only a slight inhibition compared to our results with tricyclic antidepressants as inhibitors (Dumont et al 1987;Dahl-Puustinen & Bertilsson 1987). It is possible that the inhibition of morphine glucuronidation is mediated by binding of tricyclic antidepressant at an allosteric rather than the actual catalytic site.…”

Section: Discussionmentioning

confidence: 99%

Tricyclic Antidepressants Inhibit Opioid Receptor Binding in Human Brain and Hepatic Morphine Glucuronidation

Wahlström

Lenhammar

Ask

et al. 1994

Pharmacology & Toxicology

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The opioid receptor binding in the human thalamic area was studied with U-69593 and naloxone as ligands for the kappa and mu receptors, respectively. The binding was inhibited by various tricyclic antidepressants including amitriptyline, nortriptyline, clomipramine and fluoxetine. The antidepressants tested had a slight selectivity for the kappa receptor type. The IC50-values for all tricyclic antidepressants tested were in the 10(-6) M concentration range. Morphine and tricyclic antidepressants are substrates of a liver microsomal uridine diphosphate glucuronyl transferase (UDPGT). The interaction of the tricyclic antidepressants with morphine glucuronidation was investigated in human liver microsomal preparations. All drugs inhibited the morphine UDPGT. In Dixon plots inhibition of the formation of morphine-3-glucuronide and morphine-6-glucuronide was non-competitive for nortriptyline, and competitive or mixed for amitriptyline and clomipramine. Lubrol PX activated the morphine-UDPGT four to five times. The degree of activation of the enzyme(s) was unaltered in presence of the inhibiting drugs. The inhibition was also observed at a tricyclic antidepressant/morphine concentration ratio close to that achieved in plasma from patients treated with these drugs.

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“…E-10-OH-NT and its conjugates, presumably glucuronides (Dumont et al 1987), represent about 30% of the given dose in the urine of depressed patients treated with AT (Biggs et al 1979;Vandel et al 1982). In addition to the oxidative reactions, AT can also undergo direct conjugation presumably to a glucuronide as this may be hydrolyzed with P-glucuronidase (Breyer-Pfaff et al 1978;Vandel et al 1982).…”

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confidence: 99%

Formation of a Quaternary N‐Glucuronide of Amitriptyline in Human Liver Microsomes

Dahl‐Puustinen

Bertilsson

1987

Pharmacology & Toxicology

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Amitriptyline N-glucuronide was isolated from urine of a patient treated with therapeutic doses of amitriptyline. The glucuronide was hydrolyzed by hot alkaline treatment and, to a lesser degree, by treatment with beta-glucuronidase. A method for the direct measurement of amitriptyline glucuronide by HPLC was developed. Human liver microsomes were shown to glucuronidate amitriptyline in the presence of UDPGA, and the activity varied 7-fold among microsomes from 13 different human livers. The glucuronidation of amitriptyline was inhibited by p-nitrophenol but not by morphine. E-10-hydroxynortriptyline, a major metabolite of amitriptyline, had only a slight inhibitory effect on the glucuronidation of amitriptyline. No significant correlation was found between the glucuronidation of amitriptyline and that of E-10-hydroxynortriptyline in the microsomes studied.

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Glucuronidation of the Enantiomers of E‐10‐Hydroxynortriptyline in Human and Rat Liver Microsomes

Cited by 16 publications

References 29 publications

Stereoselective glucuronidation of formoterol by human liver microsomes

Stereoselective glucuronidation of formoterol by human liver microsomes

Tricyclic Antidepressants Inhibit Opioid Receptor Binding in Human Brain and Hepatic Morphine Glucuronidation

Formation of a Quaternary N‐Glucuronide of Amitriptyline in Human Liver Microsomes

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