Identification of major urinary metabolites of the catechol-O-methyltransferase inhibitor entacapone in the dog

Wikberg, Tom; Ottoila, Pekka; Taskinen, Jyrki

doi:10.1007/bf03190186

Cited by 51 publications

(79 citation statements)

References 11 publications

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“…In addition, the hydroxyl group (14-hydroxyl of andrographolide) at position 14 was dehydrated, and a new carbon-carbon double bond was formed at 14(13). This appears to be a rare metabolic reaction, but it has been cited in the literature (Wikberg and Taskinen, 1993;Yoshino et al, 1993). It appears that this may be the main metabolic pathway of andrographolide in rats and somehow could explain why the drug could be easily eliminated from the body.…”

Section: Discussionmentioning

confidence: 97%

Identification of a Rare Sulfonic Acid Metabolite of Andrographolide in Rats

Li²,

Gao³

et al. 2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Andrographolide is widely used in clinic as an anti-inflammatory and antibiotic drug. In this paper, the metabolites of andrographolide in rats after single oral doses of 120 mg/kg were investigated. The structures of the metabolites were elucidated by high-resolution mass spectra, NMR spectroscopy including 1 H NMR, 13 C NMR, and two-dimensional NMR, through comparison to a synthetic standard. The main metabolite of andrographolide in rats was 14-deoxy-12(R)-sulfo andrographolide. In the proposed mechanism, the ␤-carbon of ␣, ␤-unsaturated carbonyl was attacked by sulfonic acid, to form the sulfonate compound. This was a rare metabolic reaction. It may be the main metabolic pathway of andrographolide in rats. The polarity of the sulfonate metabolite increased greatly and could be easily eliminated from body.

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Section: Discussionmentioning

confidence: 97%

Identification of a Rare Sulfonic Acid Metabolite of Andrographolide in Rats

Li²,

Gao³

et al. 2003

Drug Metab Dispos

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“…In urine, the 3-O-␤-glucuronic conjugates of tolcapone (ϳ13%) and its derivative N-acetyl amino (ϳ5.7%) are the predominant metabolites found (Jorga et al, 1999). Regarding entacapone, the only metabolite described in human plasma is the Zisomer (ϳ5%) (Wikberg et al, 1993;Keranen et al, 1994); however, in human urine, besides the Z-isomer (ϳ25%), the 3-O-␤-glucuronic acid derivative (ϳ70%) is the prevalent metabolite (Wikberg et al, 1993).No methylation products of entacapone were detected in human plasma or urine, possibly because the nitro group of entacapone hinders methylation of the catechol (Wikberg et al, 1993). As an alternative to molecular conjugation with endogenous species like glucuronidation, sulfation, methylation, glutathione conjugation, and acetylation (phase II drug metabolism reactions), these drugs could undergo oxidation, reduction, and hydroxylation (phase I drug metabolism reactions); however, such phase I metabolites are minor (Wikberg et al, 1993;Jorga et al, 1999).…”

mentioning

confidence: 99%

“…Regarding entacapone, the only metabolite described in human plasma is the Zisomer (ϳ5%) (Wikberg et al, 1993;Keranen et al, 1994); however, in human urine, besides the Z-isomer (ϳ25%), the 3-O-␤-glucuronic acid derivative (ϳ70%) is the prevalent metabolite (Wikberg et al, 1993).…”

mentioning

confidence: 99%

Human Metabolism of Nebicapone (BIA 3-202), a Novel Catechol-O-Methyltransferase Inhibitor: Characterization of in Vitro Glucuronidation

Loureiro

Bonifácio²,

Fernandes-Lopes³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Nebicapone (BIA 3-202; 1-[3,4-dihydroxy-5-nitrophenyl]-2-phenylethanone), a novel catechol-O-methyltransferase inhibitor, is mainly metabolized by glucuronidation. The purpose of this study was to characterize the major plasma metabolites of nebicapone following p.o. administration of nebicapone to healthy volunteers, and to determine the human UDP-glucuronosyltransferase (UGT) enzymes involved in nebicapone glucuronidation. Plasma samples were collected as part of a clinical trial at different time points postdose and were analyzed for nebicapone and its metabolites using a validated method consisting of a solid-phase extraction, followed by high-performance liquid chromatography/mass spectrometry detection. The primary metabolic pathways of nebicapone in humans involve mainly 3-O-glucuronidation, the major early metabolite, and 3-O-methylation, the predominant late metabolite. Of the nine commercially available recombinant UGT enzymes studied (UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15), only UGT1A9 exhibited high nebicapone glucuronosyltransferase specific activity (24.3 ؎ 1.3 nmol/mg protein/min). UGT1A6, UGT1A7, UGT1A8, UGT1A10, UGT2B7, and UGT2B15 exhibited low activity (0.1-1.1 nmol/mg protein/min), and UGT1A1 and UGT1A3 showed extremely low activities (less than 0.03 nmol/mg protein/min). The results show that nebicapone is mainly glucuronidated in humans and that multiple UGT enzymes are involved in this reaction.L-3,4-dihydroxyphenylalanine (L-DOPA) therapy has revolutionized treatment of idiopathic Parkinson's disease (PD) by providing a p.o. administered source of dopamine precursor with ready access to the brain, and it remains the most widely used palliative drug for PD. However, L-DOPA is metabolized in the periphery by aromatic Lamino acid decarboxylase (AADC) and catechol-O-methyltransferase (COMT) enzymes, reducing brain availability. Therefore, an improvement in L-DOPA therapy is provided by a combination treatment of L-DOPA with an AADC inhibitor plus a COMT inhibitor, effectively increasing its availability to the brain (Backstrom et al., 1989).Second-generation COMT inhibitors entacapone and tolcapone ( Fig. 1) have proven beneficial when used together with L-DOPA and an AADC inhibitor, such as carbidopa or benserazide, in the medical treatment of patients with PD (Dingemanse et al., 1995;Dingemanse, 1997;Heikkinen et al., 2001Heikkinen et al., , 2002. When metabolized, these nitrocatechol derivatives are extensively conjugated, usually undergo direct glucuronidation catalyzed by UDP-glucuronosyltransferases (UGT), and are then rapidly excreted in the urine (Lautala et al., 1997). Additionally, both methylation and sulfation compete with glucuronidation for conjugation of the adjacent phenolic hydroxyls (Lautala et al., 1997). Major metabolites of tolcapone in human plasma are the 3-O-␤-glucuronic acid (ϳ18.6%) and the 3-O-methyl conjugate (ϳ2.1%). In urine, the 3-O-␤-glucuronic conjugates of tolcapone (ϳ13%) and its derivative N-acetyl amino (ϳ5.7...

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“…The metabolic pathways of nebicapone appear to be similar to those of other nitrocatechol inhibitors, such as entacapone and tolcapone, which primarily involve glucuronidation [21,22]. Catechols are metabolized by oxidative and conjugation reactions, with nitrocatechols being glucuronidated at lower rates than other catechols.…”

Section: Discussionmentioning

confidence: 92%

“…Differences between species concerning the metabolism of nitrocatechol derivatives have also been described for entacapone. Sulphated conjugates of entacapone and its metabolites were found in dog and rat urine, but only traces in human urine [27]. The complete lack of nebicapone sulphation in the mouse may reflect a low affinity of mouse sulfotransferase enzymes towards nebicapone.…”

Section: Discussionmentioning

confidence: 95%

Species differences in pharmacokinetic and pharmacodynamic properties of nebicapone

Bonifácio¹,

Loureiro²,

Torrão³

et al. 2009

Biochemical Pharmacology

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The present study was designed to characterize pharmacodynamic and pharmacokinetic properties of nebicapone in rats and mice. Upon oral administration of nebicapone the extent of mouse liver catechol-O-methyltransferase (COMT) inhibition is half that in the rat.Nebicapone was rapidly absorbed reaching plasma C max within 30 min and being completely eliminated by 8 h. Nebicapone was metabolized mainly by glucuronidation and methylation in both species, but rat had an extra major metabolite, resulting from sulphation. Administration of nebicapone by the intraperitoneal route significantly increased compound AUC in the rat while in the mouse a significant increase in AUC of metabolites was observed. These results show that nebicapone exhibited marked species differences in bioavailability and metabolic profile. Evaluation of COMT activity in rat and mice liver homogenates revealed that both had similar methylation efficiencies (K cat values, respectively 7.3 and 6.4 min -1 ), but rat had twice active enzyme units as the mouse (molar equivalency respectively 150 and 83).Furthermore, nebicapone inhibited rat liver COMT with a lower K i than mouse liver COMT (respectively 0.2 versus 1.2 nM). In conclusion, the results from the present study show that mice and rats respond differently to COMT inhibition by nebicapone. The more pronounced inhibitory effects of nebicapone in the rat may be related to an enhanced oral availability and less pronounced metabolism of nebicapone in this specie, but also concerned with the predominant expression of S-COMT over MB-COMT, the latter of which is less sensitive to inhibition by nebicapone than the former.

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Identification of major urinary metabolites of the catechol-O-methyltransferase inhibitor entacapone in the dog

Cited by 51 publications

References 11 publications

Identification of a Rare Sulfonic Acid Metabolite of Andrographolide in Rats

Identification of a Rare Sulfonic Acid Metabolite of Andrographolide in Rats

Human Metabolism of Nebicapone (BIA 3-202), a Novel Catechol-O-Methyltransferase Inhibitor: Characterization of in Vitro Glucuronidation

Species differences in pharmacokinetic and pharmacodynamic properties of nebicapone

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