Mephenytoin dosing

As with the hydroxylation of bufuralol, the hydroxylation is stereo-selective. Thus, only S-mephenytoin undergoes aromatic 4-hydroxy lation, and only this route is affected by the polymorphism. The R isomer undergoes N-demethylation. Poor metabolizers may suffer an exaggerated central response when given therapeutic doses (Fig. 5.29). 

Tyrbing et al. [166] studied the stereoselective disposition of omeprazole and its formed 5-hydroxy metabolite in five poor metabolizers, and five extensive metabolizers of 5-mephenytoin. After a single oral dose of omeprazole (20 mg), the plasma concentrations of the separated enantiomers of the parent drug and the 5-hydroxy metabolite were determined for 10 h after drug intake. In poor metabolizers, the area under the plasma concentration versus time curve [AUC(0-8)] of (+) omeprazole was larger... 

Racemic mephenytoin is stereoselectively metabolized in man, with the (S)-enantiomer being rapidly hydroxylated in the 4 -position by CYP2C19 and the (R)-enantiomer being slowly metabolized. The OS )-mephenytoin phenotype (genotypically conferred or by administration of an inhibitor) is determined following an oral dose by measuring the ratio of (5)-mephenytoin to (//(-mephenytoin in the 0- to 8-hour urine (93). 

Mephenytoin has been extensively used for phenotyping purposes however, such use is not without practical problems. For example, sedation is often observed in PMs, especially those of small body size, e.g., children and Southeast Asians, following administration of a 100-mg dose usually used for phenotyping (178). Accordingly, a dose of 50-mg mephenytoin is often used to phenotype such individuals. A further complicating factor is that racemic mephenytoin (Mesantoin , Sandoz/Novartis, Basal, Switzerland) is not available in many parts of the world. For these reasons, other in vivo probes have been investigated. 

Nielsen KK, Brosen K, Hansen MGJ, et al. Single-dose kinetics of clomipramine relationship to the sparteine and 5-mephenytoin oxidation polymorphisms. Clin Pharmacol Ther 1994 55 518-527. 

Setiabudy R, Chiba K, Kusaka M, et al. Caution in the use of a 100 mg dose of racemic mephenytoin for phenotyping Southeastern Oriental subjects. Br J Clin Pharmacol 1992 33 665-666. 

CYP2B6 is present at low level (< 1 %) in the liver. It catalyzes bupropion hydroxylation, S-mephenytoin N-demethylation, is involved in the metabolism of cyclophosphamide, ifosfamide, mianserin and propofol. CYP2B6 6 has been associated with reduced bupropion clearance in vitro (Hesse 2004), but not in vivo whereas a moderate clearance increase was observed with CYP2B6 4 (Kirchheiner 2003). Bupropion (150 mg dose) has been proposed for phenotyping, but it is recommended to adjust dose based on subject weight (Faucette 2000). 

Blood dyscrasias, mostly dose independent, are among the most important allergic-type adverse reactions to drugs. Aplastic anemia is a serious but rare (presumably) idiosyncratic reaction. It has been reported in association with chloramphenicol, quinacrine, phenylbutazone, mephenytoin, gold compounds, and potassium chlorate. Hemolytic anemia, thrombocytopenia, and agranulocytosis may result from an unusual, acquired sensitivity to a variety of widely used drugs including aminopyrine, phenylbutazone, phenothiazines, propylthiouracil, diphenylhydantoin, penicillins, chloramphenicol, sulfisoxazole, and tolbutamide. 

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. 

Genetic polymorphisms in CYP450 isoenzymes are common. Among whites, 5-10% of the population carries a mutation of CYP450 2D6, causing them to be slow metabolizers of debriso-quine, mephenytoin, quinidine, metoprolol and dextromethorphan standard doses are more likely to be associated with adverse events as a consequence, especially when a second substrate drag is interacting. 

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... 

After taking phenobarbital 100 mg daily for 2 weeks the clearance of a single 20-mg dose of nifedipine in a cocktail also containing sparteine, mephenytoin and antipyrine was increased almost threefold in 15 healthy subjects. The nifedipine AUC was reduced by about 60%. ... 

Diazepam is primarily metabolized by hepatic cytochrome enzyme responsible for S-mephenytoin hydrox-ylation, with very little unchanged drug eliminated in the urine [1,2]. Hepatic N-demethylation results in the formation of the active metahohte desmethyldiazepam. This metabolite is hydroxylated to form oxazepam. Another minor active metabohte is temazepam. The half-life ty )of diazepam ranges from approximately 24 hours to more than 48 hours. With chronic dosing, steady-state concentrations of diazepam are achieved between 5 days and 2 weeks. The half-life is prolonged in the elderly and in patients with cirrhosis or hepatitis. 

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