Urinary Excretion of Mefenamic Acid and Its Metabolites Including Their Esterglucuronides in Preterm Infants Undergoing Mefenamic Acid Therapy.

Sato, Junichi; Kudo, Naoko; Owada, Eiji; Ito, Kaiichi; Niida, Yuichi; Umetsu, Masao; Kikuta, Takahiro; Ito, Keiji

doi:10.1248/bpb.20.443

Cited by 8 publications

(9 citation statements)

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“…These alternative phase 2-reactions include, e.g., glucuronidation and sulfation, well-known metabolic pathways for APAP. Glucuronide conjugates of 4′-OH-DF and 5-OH-DF have also been identified in urine of DF-treated patients and mice bile. , The oxidative 3′-hydroxymethyl- and 3′-carboxyl metabolites of MFA undergo glucuronidation as well, but this has not been reported for 4′-OH-MFA and 5-OH-MFA . However, the latter two metabolites have only recently been identified in vitro and have not been studied extensively…”

Section: Discussionmentioning

confidence: 99%

“…Mefenamic acid (MFA) is an NSAID shown to be nephrotoxic in some patients . Moreover, several nonclinical studies indicate that MFA is also able to induce liver toxicity both in vivo and in vitro . − In humans, MFA is directly and extensively metabolized to an acyl glucuronide and oxidized to 3′-hydroxymethyl and 3′-carboxyl metabolites, both of which are further converted into the corresponding acyl glucuronides . Additionally, GSH conjugates of MFA have been detected in vitro suggesting the formation of reactive metabolites .…”

Section: Introductionmentioning

confidence: 99%

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Human NAD(P)H:quinone Oxidoreductase 1 (NQO1)-Mediated Inactivation of Reactive Quinoneimine Metabolites of Diclofenac and Mefenamic Acid

Vredenburg

Elias

Venkataraman

et al. 2014

Chem. Res. Toxicol.

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quinone oxidoreductase 1 (NQO1) is an enzyme capable of reducing a broad range of chemically reactive quinones and quinoneimines (QIs) and can be strongly upregulated by Nrf2/Keap1-mediated stress responses. Several commonly used drugs implicated in adverse drug reactions (ADRs) are known to form reactive QI metabolites upon bioactivation by P450, such as acetaminophen (APAP), diclofenac (DF), and mefenamic acid (MFA). In the present study, the reductive activity of human NQO1 toward the QI metabolites derived from APAP and hydroxy-metabolites of DF and MFA was studied, using purified bacterial P450 BM3 (CYP102A1) mutant M11 as a bioactivation system. The NQO1-catalyzed reduction of the QI metabolites was quantified relative to spontaneous glutathione (GSH) conjugation. Addition of NQO1 to the incubations strongly reduced the formation of all corresponding GSH conjugates, and this activity could be prevented by dicoumarol, a selective NQO1 inhibitor. The GSH conjugation was strongly increased by adding human GSTP1-1 in a wide range of GSH concentrations. Still, NQO1 could effectively compete with the GST catalyzed GSH conjugation by reducing the QIs. In conclusion, we identified the QI metabolites of the 4'- and 5-hydroxy-metabolites of DF and MFA as novel substrates for human NQO1. NQO1-mediated reduction proves to be an effective pathway to detoxify these QI metabolites in addition to GSH conjugation. Genetically determined deficiency of NQO1 therefore might be a risk factor for ADRs induced by reactive QI drug metabolites.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human NAD(P)H:quinone Oxidoreductase 1 (NQO1)-Mediated Inactivation of Reactive Quinoneimine Metabolites of Diclofenac and Mefenamic Acid

Vredenburg

Elias

Venkataraman

et al. 2014

Chem. Res. Toxicol.

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“…Our search resulted in 1206 hits, of which a total of 70 manuscripts were found relevant to the scoping review (Aranda et al, 1976;Loughnan et al, 1977;Windorfer and Pringsheim, 1977;Pitlick et al, 1978;Onishi et al, 1979;Grygiel and Birkett, 1980;Brazier et al, 1981;Kawade and Onishi, 1981;Mulhall et al, 1983;Tserng et al, 1983;Ribon et al, 1984;Grasela and Donn, 1985;Choonara et al, 1989;RJ et al, 1990;Fujii et al, 1993;Hartley et al, 1993Hartley et al, , 1994Reiter and Stiles, 1993;Brammer and Coates, 1994;Vauzelle-Kervroedan et al, 1996;Sato et al, 1997;Treluyer et al, 1997;Wenzl et al, 1998;Lee et al, 1999;Touw et al, 2000;de Wildt et al, 2001de Wildt et al, , 2002de Wildt et al, , 2010Lowry et al, 2001;Allegaert et al, 2008aAllegaert et al, , 2008bAllegaert et al, , 2015Wade et al, 2008Wade et al, , 2009Wade et al, , 2009Knibbe et al, 2009;Mugabo et al, 2011;George et al, 2012;Ince et al, 2013;Kim et al, 2013;…”

Section: Resultsmentioning

confidence: 99%

“…Our search resulted in 1206 hits, of which a total of 70 manuscripts were found relevant to the scoping review ( Aranda et al, 1976 ; Loughnan et al, 1977 ; Windorfer and Pringsheim, 1977 ; Pitlick et al, 1978 ; Onishi et al, 1979 ; Grygiel and Birkett, 1980 ; Brazier et al, 1981 ; Kawade and Onishi, 1981 ; Mulhall et al, 1983 ; Tserng et al, 1983 ; Ribon et al, 1984 ; Grasela and Donn, 1985 ; Choonara et al, 1989 ; RJ et al, 1990 ; Fujii et al, 1993 ; Hartley et al, 1993 , 1994 ; Reiter and Stiles, 1993 ; Brammer and Coates, 1994 ; Vauzelle-Kervroedan et al, 1996 ; Sato et al, 1997 ; Treluyer et al, 1997 ; Wenzl et al, 1998 ; Lee et al, 1999 ; Touw et al, 2000 ; de Wildt et al, 2001 , 2002 , 2010 ; Lowry et al, 2001 ; Allegaert et al, 2008a , 2008b , 2015 ; Wade et al, 2008 , 2009 , 2009 ; Knibbe et al, 2009 ; Mugabo et al, 2011 ; George et al, 2012 ; Ince et al, 2013 ; Kim et al, 2013 ; Le Doare et al, 2013 ; Wang et al, 2013 ; Bekker et al, 2014 ; de Waal et al, 2014 ; Krekels et al, 2015 ; Mahmood, 2015 , 2017 ; Ogawa et al, 2015 ; Pain et al, 2015 ; Auriti et al, 2016 ; Cook et al, 2016 ; Momper et al, 2016 ; Flint et al, 2017 ; Hwang et al, 2017 ; Sohn et al, 2017 ; Völler et al, 2017 ; …”

Section: Exploring the Available Data On Premature Neonates: An Examp...unclassified

“…Twenty studies investigating the in vivo phase II metabolism were identified ( Windorfer and Pringsheim, 1977 ; Mulhall et al, 1983a ; Choonara et al, 1989 ; Hartley et al, 1993 , 1994 ; H et al, 1993; Reiter and Stiles, 1993 ; Brammer and Coates, 1994 ; Sato et al, 1997 ; Wenzl et al, 1998 ; Wade et al, 2008 , 2009 ; Knibbe et al, 2009 ; Krekels et al, 2015 ; Mahmood, 2015 ; Auriti et al, 2016 ; Cook et al, 2016 ; Flint et al, 2017 ; MF et al, 2017 ; Leroux et al, 2018 ; Gerhart et al, 2019 ). A large heterogenitet was found and several substrates were used and included chloramphenicol, morphine, fluconazole, lorazepam, micafungin, paracetamol, and mefenamic acid.…”

Section: Exploring the Available Data On Premature Neonates: An Examp...mentioning

confidence: 99%

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The Blind Spot of Pharmacology: A Scoping Review of Drug Metabolism in Prematurely Born Children

et al. 2022

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The limit for possible survival after extremely preterm birth has steadily improved and consequently, more premature neonates with increasingly lower gestational age at birth now require care. This specialized care often include intensive pharmacological treatment, yet there is currently insufficient knowledge of gestational age dependent differences in drug metabolism. This potentially puts the preterm neonates at risk of receiving sub-optimal drug doses with a subsequent increased risk of adverse or insufficient drug effects, and often pediatricians are forced to prescribe medication as off-label or even off-science. In this review, we present some of the particularities of drug disposition and metabolism in preterm neonates. We highlight the challenges in pharmacometrics studies on hepatic drug metabolism in preterm and particularly extremely (less than 28 weeks of gestation) preterm neonates by conducting a scoping review of published literature. We find that >40% of included studies failed to report a clear distinction between term and preterm children in the presentation of results making direct interpretation for preterm neonates difficult. We present summarized findings of pharmacokinetic studies done on the major CYP sub-systems, but formal meta analyses were not possible due the overall heterogeneous approaches to measuring the phase I and II pathways metabolism in preterm neonates, often with use of opportunistic sampling. We find this to be a testament to the practical and ethical challenges in measuring pharmacokinetic activity in preterm neonates. The future calls for optimized designs in pharmacometrics studies, including PK/PD modeling-methods and other sample reducing techniques. Future studies should also preferably be a collaboration between neonatologists and clinical pharmacologists.

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Saure antipyretische Analgetika

Waldvogel¹

2001

Analgetika Antinozizeptiva Adjuvanzien

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Urinary Excretion of Mefenamic Acid and Its Metabolites Including Their Esterglucuronides in Preterm Infants Undergoing Mefenamic Acid Therapy.

Cited by 8 publications

References 0 publications

Human NAD(P)H:quinone Oxidoreductase 1 (NQO1)-Mediated Inactivation of Reactive Quinoneimine Metabolites of Diclofenac and Mefenamic Acid

Human NAD(P)H:quinone Oxidoreductase 1 (NQO1)-Mediated Inactivation of Reactive Quinoneimine Metabolites of Diclofenac and Mefenamic Acid

The Blind Spot of Pharmacology: A Scoping Review of Drug Metabolism in Prematurely Born Children

Saure antipyretische Analgetika

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