Identification of Novel Metoclopramide Metabolites in Humans: In Vitro and In Vivo Studies

Argikar, Upendra A.; Gómez, Javier; Ung, Din; Parkman, Henry P.; Nagar, Swati

doi:10.1124/dmd.110.033357

Cited by 27 publications

(19 citation statements)

References 24 publications

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“…All three monooxygenation products (M4a, M4b, M4c) were formed by CYP3A4 and CYP2D6 and all three were formed in NADPH dependent reactions. The M4a product if formed in vivo could be a substrate for glucuornidation to form M1 observed in a previous study (Argikar et al, 2010). …”

Section: Discussionsupporting

confidence: 56%

“…Previously, metoclopramide was reported to be metabolized to both conjugated and oxidized products by the action of CYPs as well as UDP-glucuronosyltransferases and sulfotransferases (Teng et al, 1977, Argikar et al, 2010). Structurally, metoclopramide has an aromatic ring and basic nitrogens – both characteristic of substrates of CYP2D6.…”

Section: Introductionmentioning

confidence: 99%

“…Argikar et al (2010) previously identified 10 principal metabolites of metoclopramide from human urine and in vitro (in HLM and HLC) labeled M1-M10. Of these, five were conjugated to either glucuronide or sulfate at the primary amine of metoclopramide (M1, M2, M6, M7, and M8) while the other five were non-conjugated oxidation products (M3, M4, M5, M9, and M10) (for consistency, we will use the same metabolite labels as used in Argikar et al).…”

Section: Introductionmentioning

confidence: 99%

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Metoclopramide is metabolized by CYP2D6 and is a reversible inhibitor, but not inactivator, of CYP2D6

et al. 2013

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Metoclopramide is a widely used clinical drug in a variety of medical settings with rare acute dystonic events reported. The aim of this study was to assess a previous report of inactivation of CYP2D6 by metoclopramide, to determine the contribution of various CYPs to metoclopramide metabolism, and to identify the mono-oxygenated products of metoclopramide metabolism. Metoclopramide interacted with CYP2D6 with Type I binding and a Ks value of 9.56 ± 1.09 μM. CYP2D6 was the major metabolizer of metoclopramide and the two major products were N-deethylation of the diethyl amine and N-hydroxylation on the phenyl ring amine. CYPs 1A2, 2C9, 2C19, and 3A4 also metabolized metoclopramide. While reversible inhibition of CYP2D6 was noted, CYP2D6 inactivation by metoclopramide was not observed under conditions of varying concentration or varying time using Supersomes™ or pool human liver microsomes. The major metabolites of metoclopramide were N-hydroxylation and N-deethylation formed most efficiently by CYP2D6 but also formed by all CYPs examined. Also, while metoclopramide is metabolized primarily by CYP2D6, it is not a mechanism-based inactivator of CYP2D6 in vitro.

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Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metoclopramide is metabolized by CYP2D6 and is a reversible inhibitor, but not inactivator, of CYP2D6

et al. 2013

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“…Many drugs, such as metoclopramide, chloramphenicol, p-aminobenzoic acid, and zidovudine, can be metabolized into their respective glucuronides [13][14][15][16] . Fortunately, morphine-6-glucuronied possesses similar pharmacological activity as morphine and has been successfully developed as a frontline analgesic drug.…”

Section: Acta Pharmacologica Sinicamentioning

confidence: 99%

In vitro assessment of the glucose-lowering effects of berberrubine-9-O-β-D-glucuronide, an active metabolite of berberrubine

et al. 2017

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Berberrubine (BRB) is the primary metabolite of berberine (BBR) that has shown a stronger glucose-lowering effect than BBR in vivo. On the other hand, BRB is quickly and extensively metabolized into berberrubine-9-O-β-D-glucuronide (BRBG) in rats after oral administration. In this study we compared the pharmacokinetic properties of BRB and BRBG in rats, and explored the mechanisms underlying their glucose-lowering activities. C57BL/6 mice with HFD-induced hyperglycemia were administered BRB (50 mg· kg -1 ·d -1 , ig) for 6 weeks, which caused greater reduction in the plasma glucose levels than those caused by BBR (120 mg· kg -1 ·d -1 ) or BRB (25 mg· kg -1 ·d -1 ). In addition, BRB dose-dependently decreased the activity of α-glucosidase in gut of the mice. After oral administration of BRB in rats, the exposures of BRBG in plasma at 3 different dosages (10, 40, 80 mg/kg) and in urine at different time intervals (0-4, 4-10, 10-24 h) were dramatically greater than those of BRB. In order to determine the effectiveness of BRBG in reducing glucose levels, we prepared BRBG from the urine pool of rats, and identified and confirmed it through LC-MS-IT-TOF and NMR spectra. In human normal liver cell line L-O2 in vitro, treatment with BRB or BRBG (5, 20, 50 μmol/L) increased glucose consumption, enhanced glycogenesis, stimulated the uptake of the glucose analog 2-NBDG, and modulated the mRNA levels of glucose-6-phosphatase and hexokinase. However, both BBR and BRB improved 2-NBDG uptake in insulin-resistant L-O2 cells, while BRBG has no effect. In conclusion, BRB exerts a stronger glucose-lowering effect than BBR in HFD-induced hyperglycemia mice. Although BRB significantly stimulated the insulin sensitivity and glycolysis in vitro, BRBG may have a greater contribution to the glucose-lowering effect because it has much greater system exposure than BRB after oral administration of BRB. The results suggest that BRBG is a potential agent for reducing glucose levels.

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“…At present, the generation of reactive metabolites is still regarded as an important cause of drug-induced toxicity (Baillie, 2006;Guengerich and MacDonald, 2007;Argikar et al, 2010). The reactive metabolites, such as aldehyde, epoxide, and quinone, can bring about various adverse effects.…”

Section: Introductionmentioning

confidence: 99%

CPY3A4-Mediated α-Hydroxyaldehyde Formation in Saquinavir Metabolism

2013

Drug Metab Dispos

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Saquinavir (SQV) is a protease inhibitor widely used for the treatment of human immunodeficiency virus (HIV) infection. We profiled SQV metabolism in mice using a metabolomic approach. Thirty SQV metabolites were identified in mouse feces and urine, of which 20 are novel. Most metabolites observed in mice were recapitulated in human liver microsomes. Among these novel metabolites, one a-hydroxyaldehyde produced from SQV N-dealkylation was noted and verified for the first time. Meanwhile, the corresponding product (3S)-N-tert-butyldecahydro-isoquinoline-3-carboxamide and its further metabolites were identified in mouse urine. The a-hydroxyaldehyde pathway was confirmed by using semicarbazide as a trapping reagent as well. Using recombinant cytochrome P450 (CYP450) isoenzymes and Cyp3a-null mice, CYP3A was identified as the dominant enzyme contributing to the formation of a-hydroxyaldehyde. This study enhances our knowledge of SQV metabolism, which can be used for predicting drug-drug interactions and further understanding the mechanism of adverse effects associated with SQV.

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Identification of Novel Metoclopramide Metabolites in Humans: In Vitro and In Vivo Studies

Cited by 27 publications

References 24 publications

Metoclopramide is metabolized by CYP2D6 and is a reversible inhibitor, but not inactivator, of CYP2D6

Metoclopramide is metabolized by CYP2D6 and is a reversible inhibitor, but not inactivator, of CYP2D6

In vitro assessment of the glucose-lowering effects of berberrubine-9-O-β-D-glucuronide, an active metabolite of berberrubine

CPY3A4-Mediated α-Hydroxyaldehyde Formation in Saquinavir Metabolism

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