Effect of CYP2C19 genetic polymorphism on pharmacokinetics of phenytoin and phenobarbital in Japanese epileptic patients using Non-linear Mixed Effects Model approach.
OBJECTIVE
To clarify the effect of genetic polymorphism of CYP2C19 on pharmacokinetics of phenytoin and phenobarbital using a Non-linear Mixed Effects Modelling analysis in Japanese epileptic patients.


METHODS
A total of 326 serum phenytoin concentrations were collected from 132 patients, and a total of 144 serum phenobarbital concentrations were collected from 74 patients during their clinical routine care.


RESULTS
The maximal elimination rate of phenytoin decreased by 10.2% in patients with CYP2C19*1/*2 compared with patients with normal CYP2C19. The Michaelis-Menten constants in the patients with CYP2C19*1/*3 and the poor metabolizers of (CYP2C19*2/*2 or *2/*3 or *3/*3) were 27% and 54% higher than those for the patients with normal CYP2C19, respectively. The total body clearance of phenobarbital decreased by 19.3% in patients with CYP2C19*1/*3 or the poor metabolizers of CYP2C19 compared with patients with normal CYP2C19 or with CYP2C19*1/*2.


CONCLUSIONS
These findings indicated that the genetic polymorphisms of CYP2C19 contribute to the pharmacokinetic variability of phenytoin and phenobarbital, the poor metabolizers of CYP2C19, which are relatively common in Asian groups.
Yukawa
E
E
Laboratory of Evidence-Based Pharmacotherapy, College of Pharmaceutical Sciences, Daiichi University, Minami-Ku, Fukuoka, Japan. yukawa@daiichi-cps.ac.jp
Mamiya
K
K
D000328:Adult; D000465:Algorithms; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D004247:DNA / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D015233:Models, Statistical; D017711:Nonlinear Dynamics; D010634:Phenobarbital / Q000493:pharmacokinetics*; D010672:Phenytoin / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D011153:Population; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000927:Anticonvulsants; D010672:Phenytoin; D004247:DNA; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D010634:Phenobarbital