Nonlinear mixed effects model analysis of the pharmacokinetics of metoprolol in routinely treated Japanese patients.
This study was performed to estimate the mean pharmacokinetic parameters of routinely administered metoprolol in middle-aged and elderly Japanese patients. Whole blood concentration data (65 samples) at steady-state following repetitive administration to 34 patients were analyzed using a nonlinear mixed effects model. A one-compartment model was parameterized in terms of oral clearance (CL/F) and apparent volume of distribution (V/F). We evaluated the effect of polymorphic alleles (CYP2D6*2, CYP2D6*10, CYP2C19*2 and CYP2C19*3), age, gender, and heart failure on the pharmacokinetic parameters of metoprolol. The CL/F value in patients homozygous for the CYP2D6*10 allele was 64% lower than that in patients with a CYP2D6*1/*1 or *1/*2 genotype. The CL/F value in older (>70 years old) patients was 26% lower than that in younger (< or = 70 years old) patients. In addition, the V/F value in patients homozygous for the CYP2D6*10 allele was 25% lower than that in patients with the CYP2D6*1/*1 or *1/*2 genotype. On the other hand, the CYP2C19 genotype, gender, and heart failure showed no significant effects on the pharmacokinetics of metoprolol. The results suggest that the pharmacokinetic variability of metoprolol in Japanese extensive metabolizers of CYP2D6 is very large, probably because CYP2D6*10 is responsible not only for the decreased systemic clearance (CL) but also for the increased bioavailability (F) of the drug.
Graduate School of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani, Japan.
Masato
M
Taguchi
Takashi
T
Nozawa
Kouichi
K
Mizumaki
Hiroshi
H
Inoue
Katsutoshi
K
Tahara
Chihiro
C
Takesono
Yukiya
Y
Hashimoto
D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D044466:Asian People; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D006333:Heart Failure / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008790:Metoprolol / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D017711:Nonlinear Dynamics; D011110:Polymorphism, Genetic; D012737:Sex Factors
D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol