title: Pharmacokinetics of midazolam and 1'-hydroxymidazolam in Chinese with different CYP3A5 genotypes.
abstract: The CYP3A subfamily represents the most abundant cytochrome p450 in the human liver and gastrointestinal tract and plays very important role in xenobiotic metabolism. CYP3A5 is expressed in a relatively small population of whites and Orientals. We recruited 42 Chinese volunteers to determine the genotypes of CYP3A5 by polymerase chain reaction-restriction fragment length polymorphism. Genotype analyses revealed that CYP3A5*3 allele existed in 39 of 42 volunteers. CYP3A5*4 and CYP3A5*5 alleles were found in one volunteer each; and CYP3A5*2 and CYP3A5*6 alleles were not found. The most frequent CYP3A5*3 allele is known not to express CYP3A5. We excluded other genotypes of CYP3A5 to study the significance of CYP3A5*3 in midazolam pharmacokinetics. In this study, each volunteer was given a midazolam tablet (7.5 mg) orally. Blood samples were collected to analyze the time-dependent concentrations of midazolam and 1'-hydroxymidazolam by high-performance liquid chromatography. The average area under plasma concentration curve (AUC, 0-8 h) of midazolam was 9237 +/- 1050 ng-min/ml (mean +/- S.E.M.) in homozygous CYP3A5*3 (n = 14) subjects and 7934 +/- 768 ng-min/ml in heterozygous CYP3A5*1/*3 (n = 12) subjects, respectively. The average AUC (0-8 h) of 1'-hydroxymidazolam was 3748 +/- 427 ng-min/ml in homozygous CYP3A5*3 subjects and 3920 +/- 402 ng-min/ml in heterozygous CYP3A5*1/*3 subjects. The results indicated that the pharmacokinetics of midazolam and 1'-hydroxymidazolam was independent of CYP3A5 expression. Although the genetic polymorphism of CYP3A5 is well known, the results of this study suggested that the clinical consequence might be insignificant.
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, Taiwan, Republic of China.
authors.forename: Pei-Shan
authors.initials: PS
authors.lastname: Shih
authors.forename: Jin-Ding
authors.initials: JD
authors.lastname: Huang
mesh_terms: D019540:Area Under Curve; D044466:Asian People / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D008297:Male; D008874:Midazolam / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D013624:Taiwan
chemical_list: D003577:Cytochrome P-450 Enzyme System; C040081:1-hydroxymethylmidazolam; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam