Pharmacokinetics of midazolam and 1'-hydroxymidazolam in Chinese with different CYP3A5 genotypes.
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.
Shih
Pei-Shan
PS
Department of Pharmacology, College of Medicine, National Cheng Kung University, Taiwan, Republic of China.
Huang
Jin-Ding
JD
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
D003577:Cytochrome P-450 Enzyme System; C040081:1-hydroxymethylmidazolam; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam