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Overview of the Biotransformation of Antiepileptic Drugs
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
Ethotoin has two important biotransformation pathways. The first is N-deethylation by liver oxidative enzymes to form 5-phenylhydantoin, which undergoes ring opening by di-hydropyrimidinase to yield 2-phenylhydantoic acid. Only the R-form of N-dealkylated ethotoin will serve as a substrate for dihydropyrimidinase. The second route of metabolism is hydroxylation of the phenyl ring. An epoxide intermediate is probably formed as in the case with phenytoin and mephenytoin. The major hydroxylated metabolite is 3-ethyl-5-(4-hy-droxyphenyl)hydantoin, the para-substituted product. Several other hydroxylated metabolites have been found, but they are not present in significant quantities. Elimination of all the hydroxylated products is by conjugation with glucuronic acid. No metabolites of ethotoin appear to have any anticonvulsant effects.
Personalizing treatments for patients based on cardiovascular phenotyping
Published in Expert Review of Precision Medicine and Drug Development, 2022
Pharmacometabolomics has also been utilized to determine the mechanism underlying side effects associated with cardiovascular medications. The beta-blocker atenolol, a commonly prescribed cardiovascular drug, is associated with hyperglycemia and incident diabetes as side effects. Metabolomics associated baseline levels of β-alanine with a change in plasma glucose after atenolol administration and this was related to a SNP in dihydropyrimidinase, an enzyme involved in β-alanine formation [87]. Other investigators who focused on acylcarnitines in patients treated with atenolol found that arachidonoyl-carnitine (C20:4) associated with a higher blood glucose level, lower plasma high-density lipoprotein cholesterol, and less of a therapeutic effect from atenolol than what was observed in individuals who did not have measurable levels of arachidonoyl-carnitine [88].
Proteomics-inspired precision medicine for treating and understanding multiple myeloma
Published in Expert Review of Precision Medicine and Drug Development, 2020
Matthew Ho, Giada Bianchi, Kenneth C. Anderson
Bai et al. performed nano liquid chromatography-electrospray ionization-tandem mass spectrometry (nanoLC-ESI-MS/MS) on the serum of 62 patients with newly diagnosed (ND) MM, 38 patients in CR and very good partial response (VGPR), and 43 patients with refractory and relapsed (RR) disease; and compared them against 64 healthy controls [134]. The group identified a four-peptide panel (dihydropyrimidinase-like 2, fibrinogen α-chain, platelet factor 4, and α-fetoprotein) that predicted MM with a sensitivity and specificity of 93.55% and 92.19%, respectively [134]. Importantly, this four-peptide model could be used to differentiate ND and refractory relapsed (RR) patients from healthy controls or patients with CR or VGPR, highlighting its utility in monitoring MM disease progression and treatment response [134].
Glioma tumor proteomics: clinically useful protein biomarkers and future perspectives
Published in Expert Review of Proteomics, 2020
Saicharan Ghantasala, Kishore Gollapalli, Sridhar Epari, Aliasgar Moiyadi, Sanjeeva Srivastava
Posttranslational modifications play a key role in metabolism by either activating or inactivating the enzymes or proteins. Changes in the protein tyrosine nitration in GBMs were studied using 2DE and LC-MS/MS-based approaches and identified increased nitration of Sorcin and beta-tubulin proteins in GBMs with respect to control brain tissue specimens [46]. Alteration of integrin-Src-FAK, EGFR/RTK signaling pathways in GBMs was identified by Johnson et al. using phosphoproteomic analysis of GBM [47]. Dihydropyrimidinase related proteins (DRPs) levels were found to be altered in GBMs, which play a key role in the axonal guidance and neuronal differentiation [48]. Using LC-MS-based approach, Turtoi et al. identified a significant increase in the expression of collagen-VI-alpha-1 (COL6A1) in grade IV gliomas, which was further validated using Western blotting and IHC methods. Chicken chorioallantoic membrane models revealed the accessibility of COL6A1 in GBM for the antibody-based treatment [49]. GBM patients with increased expression levels of heat shock protein 27 in the tumor specimens exhibited poor prognosis than those patients with lower levels of the protein. Thus, HSP27 could be a potential prognostic marker in GBMs [31]. In another study, proteomic alterations in the sub-group of GBMs based on their proximity to the subventricular zone were studied using the iTRAQ method. This revealed significant alteration of proteins associated with cytoskeleton, lipid binding, chaperone, and cell cycle regulation in GBMs. Proteins like thymosin beta-4-like protein 3, alpha-1-antitrypsin, alpha-1-acid glycoprotein 1, haptoglobin, ferritin light chain and alpha-2-macroglobulin showed increased expression in aggressive phenotype of GBM (SVZ+ GBM) than the SVZ- GBMs [50].