The CYP3A4*18 allele, the most frequent coding variant in asian populations, does not significantly affect the midazolam disposition in heterozygous individuals.
The objective of this study was to identify CYP3A4 variants in Koreans and to characterize their functional consequences in vitro and in vivo. Four single nucleotide polymorphisms were identified in 50 Koreans by direct DNA sequencing. In an additional genotyping using 248 subjects, CYP3A4(*)18 was confirmed as the most frequent coding variant in Koreans at 1.7%, and its frequency was similar to that of Asians, suggesting that CYP3A4(*)18 would be the highest coding variant in Asians. The recombinant CYP3A4.18 protein prepared in baculovirus expression system showed 67.4% lower Vmax and 1.8-fold higher K(m) for midazolam 1'-hydroxylation compared with the wild type. The mean values of Cmax and area under the concentration curve (AUC) in the CYP3A4(*)1/(*)18 and CYP3A5(*)1/(*)3 subjects (n = 8) were 63% and 32% higher than in CYP3A4(*)1/(*)1 and CYP3A5(*)1/(*)3 carriers (n = 8), respectively. Although the in vitro assay exhibited a significant reduction of the enzyme activity for midazolam, the in vivo differences associated with the CYP3A4(*)1/(*)18 tend to be low (P < 0.07 in Cmax and P < 0.09 in AUC). In summary, the heterozygous CYP3A4(*)1/(*)18 does not appear to cause a significant change of midazolam disposition in vivo; however, the clinical relevance of CYP3A4(*)18/(*)18 remains to be evaluated.
Lee
Su-Jun
SJ
Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Inje University Busan Paik Hospital, Busan, Korea.
Lee
Sang Seop
SS
Jeong
Hye-Eun
HE
Shon
Ji-Hong
JH
Ryu
Ji-Young
JY
Sunwoo
Yu Eun
YE
Liu
Kwang-Hyeon
KH
Kang
Wonku
W
Park
Young-Ju
YJ
Shin
Chi-Mann
CM
Shin
Jae-Gook
JG
D000328:Adult; D014151:Anti-Anxiety Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D044466:Asian People / Q000235:genetics*; D002384:Catalysis; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005787:Gene Frequency; D006579:Heterozygote; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D007723:Korea; D008874:Midazolam / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D013053:Spectrophotometry
D014151:Anti-Anxiety Agents; D007527:Isoenzymes; C042940:4-hydroxymidazolam; D003577:Cytochrome P-450 Enzyme System; C040081:1-hydroxymethylmidazolam; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009251:NADPH-Ferrihemoprotein Reductase; D008874:Midazolam