Drug/Small Molecule:

mephenytoin

Overview

Generic Names:	Mephentoin; Methyl Hydantoin; Methylphenetoin
Trade Names:	Epiazin; Gerot-Epilan; Insulton; Mesdontoin; Mesontoin; Methoin; Metydan; Phenantoin; Sacerno; Sedantional; Sedantoin; Sedantoinal; Triantoin
PharmGKB Accession Id:	PA450373

Description

Indication

ATC Therapeutic Category

• N03AB:Hydantoin derivatives

Pharmacology, Interactions, and Contraindications

Mechanism Of Action

Pharmacology

Isomeric SMILES Code:

In-Depth Annotations ()

1. rs3211371 at chr19:46214555 in CYP2A7P1, CYP2B6
   CYP2B6:1459C>T has been reported to reduce CYP2B6 protein expression in human liver and brain. Impact on drug response is somewhat contradictory, see VIP annotation for details.

   Variant Name:

   CYP2B6:1459C>T; CYP2B6:Arg487Cys; part of CYP2B6*1C, CYP2B6*5, CYP2B6*7

   Related Drugs:

   bupropion, efavirenz, mephenytoin, nevirapine, nicotine

   Evidence:

   http://www.pharmgkb.org/.../variant.jsp
   

Curated Annotations ()

1. rs28399504 at chr10:96512453 in CYP2C19
   This allele was examined in a European Caucasian population which had been phenotyped for mephenytoin metabolism. Based on the genotyping results the authors conclude that the defective nature of the CYP2C19*4 allele is shown by the fact that two Caucasian poor metabolizers were heterozygous for CYP2C19*2/CYP2C19*4. In vitro experiments showed no expression of CYP2C19*4 cDNA. The study calculated that the frequency of the CYP2C19*4 allele in Caucasians was 0.6%.

   Variant Name:

   CYP2C19*4; 1A>G; 99C>T; 80161A>G

   Related Drugs:

   mephenytoin

   Evidence:

   PMID:9435198
   

2. rs41291556 at chr10:96525163 in CYP2C19
   This variant is the defining SNP for CYP2C19*8 and leads to decreased activity and poor metabolizer (PM) phenotype.This variant is associated with a dramatic (approximately 90% and 70%) reduction in the metabolism of S-mephenytoin and tolbutamide in vitro.

   Variant Name:

   CYP2C19:358T>C; 12711T>C; W120R; T358C

   Related Drugs:

   mephenytoin, tolbutamide

   Evidence:

   PMID:10411572
   

3. rs17884712 at chr10:96525236 in CYP2C19
   This variant is the defining SNP for CYP2C19*9 and associated with a modest decrease in the V(max) for 4'-hydroxylation of S-mephenytoin in vitro.

   Variant Name:

   CYP2C19:431G>A; R144H

   Related Drugs:

   mephenytoin

   Evidence:

   PMID:12464799
   

4. rs6413438 at chr10:96531605 in CYP2C19
   This variant is the defining SNP for CYP2C19*10. This variant is associated with reduction in the metabolism of S-mephenytoin in vitro.

   Variant Name:

   CYP2C19:680C>T; 19153C>T; P227L

   Related Drugs:

   mephenytoin

   Evidence:

   PMID:12464799
   

5. rs56337013 at chr10:96602485 in CYP2C19
   This variant is the defining SNP for CYP2C19*5 and contributes to the S-mephenytoin poor metabolizer phenotype in caucasians and chinese. The Arg433 to Trp mutation in the heme-binding region essentially abolishes CYP2C19 activity toward S-mephenytoin and tolbutamide.

   Variant Name:

   CYP2C19:1297C>T; R433W

   Related Drugs:

   mephenytoin, tolbutamide

   Evidence:

   PMID:10022751
   

6. rs3211371 at chr19:46214555 in CYP2A7P1, CYP2B6
   The 1459C>T variant is the determining SNP of the *5 allele and a component SNP of the *7 allele. Livers from individuals with the 1459C>T variant had 8 fold lower activity as determined by demethylation of the drug mephenytoin.

   Variant Name:

   *5, 1459C>T, Arg487Cys

   Related Drugs:

   mephenytoin

   Evidence:

   http://www.cypalleles.ki.se/cyp2b6.htm
   

The following genes are in curated knowledge about this drug.

	Gene	Relationship	Evidence
	CYP1A2	PK	Publications
	CYP2A7P1		Variants
	CYP2B6	CO PD PK    GN	Publications, Variants
	CYP2C19	PK FA GN	Publications, Variants
	CYP2C9	PK	Publications
	CYP2D6	PK	Publications
	CYP3A4	CO PD PK    GN	Publications
	DRD2	CO PD PK    GN	Publications
	NR1I2	CO PD PK    GN	Publications
	NR1I3	CO PD PK    GN	Publications
	UGT1A1	CO PD PK    GN	Publications

A list of non-curated publications that mention this drug along with other genes is available.

Drug Targets

Gene		Description
ALB		(source: Drug Bank)
SCN5A		(source: Drug Bank)

The following drugs are in curated knowledge about this drug.

	Drug	Relationship	Evidence
	omeprazole	PK	Publications

A list of non-curated publications that mention this drug along with other drugs is available.

Curated Information

The following diseases are in curated knowledge about this drug.

	Disease	Relationship	Evidence
	HIV	CO PD PK    GN	Publications
	Leukemia	CO PD PK    GN	Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other diseases is available.

Curated Phenotype Datasets

These datasets are sorted alphabetically by title.

1. CYP2B6 expression and activity

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   • FA

   Submitted by Mary Relling, PharmD involving CYP2B6, and mephenytoin
2. Meperidine N-demethylation by endogenous CYP450 enzymes in human liver microsomes

   • 
   • 
   • 
   • 
   • FA

   Submitted by Mark J. Ratain, MD involving CYP2B6, CYP2C19, CYP3A4, , meperidine, mephenytoin and midazolam

Additional Datasets

These datasets are minimally curated and are sorted alphabetically by title.

1. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease

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Non-Curated Publications

A list of non-curated publications that mention this drug is available.