[Maintenance dose requirement for phenytoin is lowered in genetically impaired drug metabolism independent of concommitant use of other antiepileptics].
OBJECTIVE
To investigate the effect of genetically determined impaired drug metabolism and of the use of comedication on phenytoin maintenance dose requirement.


METHODS
Descriptive.


METHODS
In 60 patients on long-term phenytoin therapy the concentration of phenytoin in serum was measured and CYP2C9 genotyping was performed (mutant alleles of CYP2C9 are associated with impaired phenytoin metabolism). In addition, the use of other antiepileptics concurrently with phenytoin was reviewed: phenobarbital, carbamazepine and valproic acid. CYP2C9 genotype and comedication were connected to phenytoin daily dose requirement. The 60 patients were 38 men and 22 women, between 16 and 74 years of age, and all mentally disabled.


RESULTS
Genotyping revealed that of the 60 patients 38% (n = 23) carried at least one mutant CYP2C9 allele. Their mean dose of phenytoin was 199 mg dd, while the mean required maintenance dose in non-carriers (n = 37) was 287 mg dd (p < 0.01). When the use of comedication was taken into account, it appeared that the mean phenytoin daily doses in the different comedication groups did not differ significantly.


CONCLUSIONS
Patients with a genetically determined impaired phenytoin metabolism required on average a 30% lower dose than those with a normal metabolism, while the concomitant use of other antiepileptics appeared to have no effect on phenytoin dose requirement.
Ziekenhuis St Jansdal, Klinisch-Chemisch Laboratorium, Postbus 138, 3840 AC Harderwijk. j.vander.weide@stjansdal.nl
J
J
van der Weide
L S
LS
Steijns
M J
MJ
van Weelden
K
K
de Haan
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010672:Phenytoin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism
D000927:Anticonvulsants; D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase