Mephenytoin anticonvulsant

Another anticonvulsant, formerly used as a hypnotic, is 5-ethyl-5-phenyIhydantoin [631 -07-2] (Nirvanol, Mephenytoin). Its S isomer is stereo-selectively eliminated in most subjects, a fact having clinical consequences with both desired and untoward effects (119). 

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. 

A second well-studied genetic drug polymorphism involves the stereoselective aromatic (4)-hydroxylation of the anticonvulsant mephenytoin, catalyzed by CYP2C19. This polymorphism, which is also inherited as an autosomal recessive trait, occurs in 3-5% of Caucasians and 18-23% of Japanese populations. It is genetically independent of the debrisoquin-sparteine polymorphism. 

Ibeanu GC, Blaisdell J, Ferguson RJ, et al. A novel transversion in intron5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolism of the anticonvulsant drug S-mephenytoin. J Pharmacol Exp Ther 1999 290 635-640. 

The anticonvulsant drug mephenytoin exists as two enantiomers (R- and S-). Ktifer reported the stereoselective metabolism of S-mephenytoin in the dog. Later, while studying the metabolism of mephenytoin in humans, Ktifer found that the formation and urinary excretion of the 4 -hydroxymetabolite of mephenytoin is rapid during the first 24 hr after administration of the drug and this metabolite is derived almost entirely from the S-enantiomer. Unexpectedly, one of the human subjects complained of unacceptable sedation on a dose of mephenytoin. From a family study it was determined that metabolism of mephenytoin in the family of the individual who metabolized the drug poorly was inherited as an autosomal recessive trait. Subsequent population studies showed that while -3-5% of Caucasians were PMs, as many as 13-23% of Asians were PMs of mephenytoin. 

Another important group of hydrolytic enzymes are the epoxide hydrolases, also known as epoxide hydrase or epoxide hydratase, most commonly found in liver tissue. Epoxide hydrolases catalyze the hydration of arene oxides and aliphatic epoxides to their corresponding /raKt-dihydrodiols or diols, respectively, by activating a water molecule to attack one of the carbons of the arene oxide or epoxide [41]. Although one of the major metabolites of carbamazepine is the stable epoxide, this metabolite also undergoes hydrolysis to form the trans-dial metabolite (Fig. 3). Likewise, the anticonvulsants phenytoin and mephenytoin form arene oxides, which then form trans-dihy-drodiol that undergo further oxidation to form the catechols by the enzyme dihydrodiol dehydrogenase (Fig. 11) [42,43]. 

Mephenytoin is demethylated to 5-ethyl-5-phenylhydantoin (Nirvanol), which is an active anticonvulsant. Mephenytoin binds to plasma protein to the extent of 40%, with an elimination half-life of 7 hours. Mephenytoin causes sedation, whereas phenytoin does not. The incidence of dose- and time-dependent side effects of mephenytoin is lower than that seen with phenytoin. On the other hand, the incidence of severe and fatal hypersensitivity reactions is far higher than that reported for phenytoin. Therefore, mephenytoin is not the first drug of choice. It is used for the treatment of tonic-clonic, simple partial, and complex partial seizures... 

Anticonvulsants Mephenytoin (Wang et al. 2004b) Skeletal muscle relaxants Chlorzoxazone (Gurley et al. 2002,2005)... 

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