دورية أكاديمية
Metabolic activation of mefenamic acid leading to mefenamyl-S-acyl-glutathione adduct formation in vitro and in vivo in rat.
| العنوان: | Metabolic activation of mefenamic acid leading to mefenamyl-S-acyl-glutathione adduct formation in vitro and in vivo in rat. |
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| المؤلفون: | Grillo MP; Pharmacokinetics and Drug Metabolism, Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA. grillo@amgen.com, Tadano Lohr M, Wait JC |
| المصدر: | Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2012 Aug; Vol. 40 (8), pp. 1515-26. Date of Electronic Publication: 2012 May 10. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics, etc.] Country of Publication: United States NLM ID: 9421550 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-009X (Electronic) Linking ISSN: 00909556 NLM ISO Abbreviation: Drug Metab Dispos Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [Bethesda, Md., etc., American Society for Pharmacology and Experimental Therapeutics, etc.] |
| مواضيع طبية MeSH: | Biotransformation*, Glutathione/*pharmacokinetics , Mefenamic Acid/*pharmacokinetics, Animals ; Chromatography, Liquid ; Hepatocytes/metabolism ; Humans ; In Vitro Techniques ; Rats ; Tandem Mass Spectrometry |
| مستخلص: | Carboxylic acid-containing nonsteroidal anti-inflammatory drugs (NSAIDs) can be metabolized to chemically reactive acyl glucuronide and/or S-acyl-CoA thioester metabolites capable of transacylating GSH. We investigated the metabolism of the NSAID mefenamic acid (MFA) to metabolites that transacylate GSH, leading to MFA-S-acyl-GSH thioester (MFA-SG) formation in incubations with rat and human hepatocytes and in vivo in rat bile. Thus, incubation of MFA (1-500 μM) with rat hepatocytes led to the detection of MFA-1-β-O-acyl glucuronide (MFA-1-β-O-G), MFA-S-acyl-CoA (MFA-SCoA), and MFA-SG by liquid chromatography-tandem mass spectrometric analysis. The C(max) of MFA-SG (330 nM; 10-min incubation with 100 μM MFA) was 120- to 1400-fold higher than the C(max) of drug S-acyl-GSH adducts detected from studies with other carboxylic acid drugs to date. MFA-SG was also detected in incubations with human hepatocytes, but at much lower concentrations. Inhibition of MFA acyl glucuronidation in rat hepatocytes had no effect on MFA-SG formation, whereas a 58 ± 1.7% inhibition of MFA-SCoA formation led to a corresponding 66 ± 3.5% inhibition of MFA-SG production. Reactivity comparisons with GSH in buffer showed MFA-SCoA to be 80-fold more reactive than MFA-1-β-O-G forming MFA-SG. MFA-SG was detected in MFA-dosed (100 mg/kg) rat bile, where 17.4 μg was excreted after administration. In summary, MFA exhibited bioactivation in rat and human hepatocytes and in vivo in rat, leading to reactive acylating derivatives that transacylate GSH. The formation of MFA-SG in hepatocytes was shown not to be mediated by reaction with MFA-1-β-O-G, and not solely by MFA-SCoA, but perhaps also by intermediary MFA-acyl-adenylate formation, which is currently under investigation. |
| المشرفين على المادة: | 367589PJ2C (Mefenamic Acid) GAN16C9B8O (Glutathione) |
| تواريخ الأحداث: | Date Created: 20120512 Date Completed: 20121119 Latest Revision: 20141120 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1124/dmd.112.046102 |
| PMID: | 22577085 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1521-009X |
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| DOI: | 10.1124/dmd.112.046102 |