Phenytoin 3- methyl

Thermal decomposition of tetramethylammonium or trimethylanilinium salts was described for phenytoin methylation prior to its GC analysis in plasma [556] and diethyl-stilbestrol in biological fluids [557], Usually a liquid or homogenized sample is extracted into toluene, the respective tetrasubstituted ammonium hydroxide is added and the liquid phase is injected at 260—290°C. 

A further group of AT-[(acyloxy)methyl] pro-moieties contains acidic and/or lipid-like substituents. Here again, most published results concern phenytoin. Thus, some phenytoin-lipid conjugates such as 8.183 and 8.186 (with R = various fatty acyl moieties) were reported [233]. Such prodrugs are, of course, insoluble in water but formed dispersions when briefly sonicated in EtOH/water mixtures containing sodium taurodeoxycholate. No significant hydrolysis was seen in buffer or plasma. In contrast, incubation with pancreatic lipase yielded the bis-deacyl derivatives (i.e., 8.182 and 8.185, respectively), with subsequent liberation of phenytoin the time for 50% liberation of phenytoin varied from 20 to 200 min under the conditions of the studies [233][234], The intermediates 8.182, 8.184, and 8.185 were also substrates for human and rat plasma hydrolases. 

Fig. 9.7. a) Mechanism of activation of (phenytoin-3-yl)methyl phosphate (9.25) to release phenytoin. Phosphoric acid ester hydrolysis is mediated by alkaline phosphatase, b) (Phospho-ryloxy)methyl prodrugs of tertiary amines, whose activation occurs by the same two-step mechanism shown in a [79]. 

In previous chapters, we discussed the hydrolysis of a number of esters of A-(hydroxymethyl)phcnytoin, namely esters of organic acids (7V-acyloxy-methyl derivatives, Sect. 8.7.3) or inorganic acids (Sect. 9.3.2). Hydrolysis of these potential prodrugs released 3-(hydroxymethyl)phenytoin (11.45), whose breakdown to phenytoin and formaldehyde was also investigated per se [79], The latter reaction followed pseudo-first-order kinetics. At pH 7.4, the f1/2 values were 4.7 and 1.6 s at 25° and 37°, respectively. The tm values decreased tenfold for each increase of pH by one unit, which, together with the absence of any buffer catalysis, indicates catalysis by the HO- anion. 

Alkylation of the hydantoin (89-2) from benzaldehyde with ethyl iodide takes place at the imide nitrogen to afford ethitoin (89-3) [93]. In much the same vein, treatment of the hydantoin (89-5) from propiophenone with methyl iodide (89-5) in the presence of a base affords mephenytoin (89-6) [94]. Replacement of the quite acidic imide proton by an aUcyl group is not required for activity the well-known anticonvulsant phenytoin (89-8) consists of simply the hydantoin obtained from benzophenone (89-7) [95] this is often formulated as its sodium salt. 

Succinylcholine solutions contained 0.05% (w/v) methyl- -hydroxybenzoate as stabilizer. Phenytoin (sodium salt) and decanol were supplied by Sigma (St. Louis, MO) other materials were tricaprylylmethylammoniura chloride or Aliquat 336S (General Mills Chemicals, Inc., Kankakee, IL). Solutions of sodium phenytoin were prepared by serial dilution while keeping both pH and ionic strength at constant values, 10 and 0.1 mol/1, respectively. The selectivity coefficients were determined at pH 10.0 and 0.1 mol/1 ionic strength, both adjusted with borax-NaOH buffer solution of pH 10.0. 

G1azko 7 reviewed same early studies on the gas chromatographic assay of phenytoin. These included derivatization with diazomethane S, the use of trimethylsilyl derivative /50, on col linn methyl at ion using tetramethyl ammonium hydroxide51 and trimethylanilinium hydroxide5. ... 

Folate (pteroylglutamic acid) is essential for the synthesis and methylation of DNA during fetal and early postnatal development (Nunn et al., 1986). Folate deficiency may result from poor diet, malabsorption, from treatment with anticonvulsant drugs such as phenytoin or primidone, as well as from antifolate drugs such as methotrexate. Folate deficiency during pregnancy leads to an increased prevalence of fetal malformations such as spina bifida and related neural tube defects. Findings... 

Two standard plasma solutions are used, the first containing 50 jag/ml of phenobarbitone and 20 lag/ml each of primidone and phenytoin, and die second containing 100 jag/ml of phenobarbitone and 50 lag/ml each of primidone and phenytoin. The internal standard used is either 5-methyl-5-phenylhydantoin or 5-p-methylphenyl-5-phenyl-hydantoin. 

Clinton, M.E., Misulis, K.E., Dettbam, W-D. (1988). Effects of phenytoin, ketamine, and atropine methyl nitrate in preventing neuromuscular toxicity of acetylcholinesterase inhibitors soman and diisopropylphosphorofluoridate. J. Toxicol. Environ. Health 24 439-49. 

Figure 29 Structure of S-adenosylmethionine (SAM) and S-adenosylhomo-cysteine (SAH). A generalized methylation reaction and the methylation of phenytoin catechol and nicotine.

Diclofenac (C4 -hydroxylation), phenytoin (C4 -hydrosylation), tolbutamide (p-methyl-hydroxylation)... 

Also analyzed acebutolol, acepromazine, acetaminophen, acetazolamide, acetophenazine, albuterol, amitriptyline, amobarbital, amoxapine, antipsrrine, atenolol, atropine, azata-dine, baclofen, benzocaine, bromocriptine, brompheniramine, brotizolam, bupivacaine, buspirone, butabarbital, butalbital, caffeine, carbamazepine, cetirizine, chlorqyclizine, chlordiazepoxide, chlormezanone, chloroquine, chlorpheniramine, chlorpromazine, chlorpropamide, chlorprothixene, chlorthalidone, chlorzoxazone, cimetidine, cisapride, clomipramine, clonazepam, clonidine, clozapine, cocaine, codeine, colchicine, qyclizine, (yclo-benzaprine, dantrolene, desipramine, diazepam, diclofenac, diflunisal, diltiazem, diphenhydramine, diphenidol, dipheno late, dipyridamole, disopyramide, dobutamine, doxapram, doxepin, droperidol, encainide, ethidium bromide, ethopropazine, fenoprofen, fentanyl, flavoxate, fluoxetine, fluphenazine, flurazepam, flurbiprofen, fluvoxamine, fii-rosemide, glutethimide, glyburide, guaifenesin, haloperidol, homatropine, hydralazine, hydrochlorothiazide, hydrocodone, hydromorphone, hydro g chloroquine, hydroxyzine, ibuprofen, imipramine, indomethacin, ketoconazole, ketoprofen, ketorolac, labetalol, le-vorphanol, lidocaine, loratadine, lorazepam, lovastatin, loxapine, mazindol, mefenamic acid, meperidine, mephenytoin, mepivacaine, mesoridazine, metaproterenol, methadone, methdilazine, methocarbamol, methotrexate, methotrimeprazine, methoxamine, methyl-dopa, methylphenidate, metoclopramide, metolazone, metoprolol, metronidazole, midazolam, moclobemide, morphine, nadolol, nalbuphine, naloxone, naphazoline, naproxen, nifedipine, nizatidine, norepinephrine, nortriptyline, oxazepam, oxycodone, oxymetazo-line, paroxetine, pemoline, pentazocine, pentobarbital, pentoxifylline, perphenazine, pheniramine, phenobarbital, phenol, phenolphthalein, phentolamine, phenylbutazone, phenyltoloxamine, phenytoin, pimozide, pindolol, piroxicam, pramoxine, prazepam, prazosin, probenecid, procainamide, procaine, prochlorperazine, procyclidine, promazine, promethazine, propafenone, propantheline, propiomazine, propofol, propranolol, protriptyline, quazepam, quinidine, quinine, racemethorphan, ranitidine, remoxipride, risperidone, salicylic acid, scopolamine, secobarbital, sertraline, sotalol, spironolactone, sulfinpyrazone, sulindac, temazepam, terbutaline, terfenadine, tetracaine, theophylline, thiethyl-perazine, thiopental, thioridazine, thiothixene, timolol, tocainide, tolbutamide, tolmetin, trazodone, triamterene, triazolam, trifluoperazine, triflupromazine, trimeprazine, trimethoprim, trimipramine, verapamil, warfarin, xylometazoline, yohimbine, zopiclone... 

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