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Mephenytoin
Published in Stanley R. Resor, Henn Kutt, The Medical Treatment of Epilepsy, 2020
R-Nirvanol, which usually constitutes over 90% of the combined steady-state MHT/nirvanol levels in serum (2), provides most of the antiepileptic efficacy and the adverse effects. Up to 85% of nirvanol is slowly excreted metabolically unchanged with a rate that is to some degree proportional to creatinine clearance (6,8). Thus the state of renal function becomes a cofactor in determining nirvanol half-life and the dose and blood level ratios in MHT therapy. As the pKa of nirvanol is 8.5, alkalinization of urine will enhance its excretion (8), a point relevant in treatment of MHT overdose. This long half-life of nirvanol (4 days) makes MHT a suitable drug to give once per day. It is given at bedtime because of the prominent peak appearance of the MHT itself shortly after administration. Steady state following initial administration will not be achieved for approximately 3 weeks, which must be taken into account when one is switching from a shorter half-life drug to MHT, lest too rapid withdrawal of the prior drug leave the patient unprotected. MHT is not extensively bound to serum albumin, with 60% being free in serum and saliva. Nirvanol is 70% free in serum and saliva (3). Changes in free drug levels are not clinically significant in various disease states nor as a result of comedication with drugs tightly bound to serum albumin.
Overview of the Biotransformation of Antiepileptic Drugs
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
The second major biotransformation that mephenytoin undergoes is N-demethylation at the three position to form 5-ethyl-5-phenylhydantoin (Nirvanol). Nirvanol is the name of an old drug introduced as a hypnotic but removed from therapy because of its toxicity. Nirvanol is an effective anticonvulsant drug with a half-life much longer than that of mephenytoin (approximately 100 h and 7 h, respectively). Therefore, during chronic administration of mephenytoin, Nirvanol is preferentially formed and accumulates because of its long half-life. Thus, the active metabolite accounts for most of the antiepileptic effectiveness, and probably toxicity, of mephenytoin. There is stereospecificity in the further disposition of Nirvanol. The dextro-form has a shorter half-life and is more rapidly excreted in urine.
Quantitative in vitro phenotyping and prediction of drug interaction potential of CYP2B6 substrates as victims
Published in Xenobiotica, 2018
Raghava Choudary Palacharla, Ramakrishna Nirogi, Venkatesham Uthukam, Arunkumar Manoharan, Ranjith Kumar Ponnamaneni, Ilayaraja Kalaikadhiban
The test compounds include artemisinin, bupropion, clopidogrel, ketamine, selegiline and ticlopidine that were obtained from Sigma-Aldrich (St. Louis, MO) and sertraline obtained from Tocris (Ellisville, MO). Furafylline, tranylcypromine, montelukast, quinidine, 4-methylpyrazole, azamulin, Bovine serum albumin (BSA, Lot # SLBR5497V, fatty acid and globulin free) and Nicotinamide adenine dinucleotide phosphate reduced (NADPH) were procured from Sigma-Aldrich (St. Louis, MO). Dextrorphan, hydroxy bupropion, hydroxy diclofenac, sulfaphenazole and N-3-benzyl nirvanol were purchased from BD Gentest (Woburn, MA). Desethyl amodiaquine was purchased from Cypex (Dundee, UK). Human liver microsomes (HLM), mixed gender pool of 50 donors (Lot # 1210267), were purchased from Xenotech, LLC (LENEXA, KS). Recombinant expressed CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 enzymes and control preparations from baculovirus-infected sf9 insect cells (Supersomes) were purchased from BD Gentest (Woburn, MA). Cytochrome b5 was co-expressed in CYP2A6, 2B6, 2C8, 2C9, 2E1 and 3A4 and cytochrome c reductase was co-expressed in all enzymes. Dialysis membrane strips (MWCO 12–14 kDa, batch # 2350 (10–15)) and High Throughput (HT) dialysis assembly used for protein binding studies were procured from HT Dialysis (Galesferry, CT). All other reagents were obtained from standard suppliers.