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Nonlinear mixed effects model analysis of the pharmacokinetics of metoprolol in middle‐aged and elderly Japanese patients
Author(s) -
Taguchi M.,
Nozawa T.,
Mizumaki K.,
Inoue H.,
Tahara K.,
Takesono C.,
Hashimoto Y.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.122
Subject(s) - metoprolol , pharmacokinetics , cyp2d6 , medicine , nonmem , cyp2c19 , pharmacology , clinical pharmacology , volume of distribution , gastroenterology , cytochrome p450 , metabolism
Purpose This study was performed to characterize the factors involved in the pharmacokinetic variability of routinely administered metoprolol in middle‐aged and elderly Japanese patients. Methods The 65 whole blood concentration data after repetitive administration to 34 patients were analyzed using the nonlinear mixed effects model (NONMEM) program. A one‐compartment model with rapid absorption was parameterized in terms of oral clearance (CL/F) and apparent volume of distribution. We investigated the effect of polymorphic alleles of cytochrome P450 ( CYP2D6*2 , CYP2D6*10 , CYP2C19*2 and CYP2C19*3 ), age, gender, and heart failure on the pharmacokinetic parameters of metoprolol. Results The CL/F was 64% decreased in the patients homozygous for the CYP2D6*10/*10 , as compared with the patients with the CYP2D6*1/*1 or *1/*2 genotype. In addition, the CL/F value in the older (> 70‐year‐old) patients was 26% lower than that in the younger (<70‐year‐old) patients. On the other hand, the genotype of CYP2C19, gender, and heart failure showed no significant effect on the pharmacokinetic parameters of metoprolol. Conclusion These findings suggested that a lower dose of metoprolol may be used in the elderly Japanese patients with the CYP2D6*10 allele. Clinical Pharmacology & Therapeutics (2004) 75 , P32–P32; doi: 10.1016/j.clpt.2003.11.122