Premium
Pharmacokinetics of midazolam in korean healthy subjects with CYP3A4 wild type and *18 variant
Author(s) -
Kang W.,
Jung H.,
Yoon Y.,
Liu K.,
Cha I.,
Shin J.
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.2003.11.252
Subject(s) - midazolam , cyp3a4 , pharmacokinetics , cmax , pharmacology , cyp2d6 , cytochrome p450 , cyp3a , population , oral administration , genotype , clinical significance , medicine , chemistry , metabolism , biochemistry , environmental health , sedation , gene
CYP3A4*18, a cytochrome P450 3A4 allelic variant has been proposed to increase the catalytic activity in human cDNA transformed E. coli . This study was designed to evaluate the clinical relevance of CYP3A4*18 allele on the pharmacokinetics of midazolam, a proven drug for CYP3A4. Six Korean subjects with heterozygous CYP3A4*18 and 6 with wild‐type CYP3A4 were participated. After a single oral administration of midazolam (7.5mg), blood samples were serially collected up to 24hr, and plasma concentrations of midazolam and two major metabolites (1‐hydroxy and 4‐hydroxy midazolam) were measured by LC/MS/MS. The mean AUC inf of midazolam in subjects with heterozygous CYP3A4*18 (116±46 ng·hr/ml) was 14% lower than that in subjects with wild‐type genotype (135±65 ng·hr/ml), but not statistically significant. There were no differences between two groups in the pharmacokinetic parameters (AUC inf , C max , half‐life, clearance) and the metabolic ratios (AUC inf,1‐OH or 4‐OH /AUC inf, parent ) of both metabolites. These results represent that CYP3A4*18 allele rarely found in Korean population with low frequency (<2%) is unlikely to affect the disposition and metabolism of midazolam. Thus the clinical consequences seem to be negligible. Clinical Pharmacology & Therapeutics (2004) 75 , P67–P67; doi: 10.1016/j.clpt.2003.11.252