CYP3A4*16 and CYP3A4*18 alleles found in East Asians exhibit differential catalytic activities for seven CYP3A4 substrate drugs.
CYP3A4, the major form of cytochrome P450 (P450) expressed in the adult human liver, is involved in the metabolism of approximately 50% of commonly prescribed drugs. Several genetic polymorphisms in CYP3A4 are known to affect its catalytic activity and to contribute in part to interindividual differences in the pharmacokinetics and pharmacodynamics of CYP3A4 substrate drugs. In this study, catalytic activities of the two alleles found in East Asians, CYP3A4*16 (T185S) and CYP3A4*18 (L293P), were assessed using the following seven substrates: midazolam, carbamazepine, atorvastatin, paclitaxel, docetaxel, irinotecan, and terfenadine. The holoprotein levels of CYP3A4.16 and CYP3A4.18 were significantly higher and lower, respectively, than that of CYP3A4.1 when expressed in Sf21 insect cell microsomes together with human NADPH-P450 reductase. CYP3A4.16 exhibited intrinsic clearances (V(max)/K(m)) that were lowered considerably (by 84-60%) for metabolism of midazolam, carbamazepine, atorvastatin, paclitaxel, and irinotecan compared with CYP3A4.1 due to increased K(m) with or without decreased V(max) values, whereas no apparent decrease in intrinsic clearance was observed for docetaxel. On the other hand, K(m) values for CYP3A4.18 were comparable to those for CYP3A4.1 for all substrates except terfenadine; but V(max) values were lower for midazolam, paclitaxel, docetaxel, and irinotecan, resulting in partially reduced intrinsic clearance values (by 34-52%). These results demonstrated that the impacts of both alleles on CYP3A4 catalytic activities depend on the substrates used. Thus, to evaluate the influences of both alleles on the pharmacokinetics of CYP3A4-metabolized drugs and their drug-drug interactions, substrate drug-dependent characteristics should be considered for each drug.
Maekawa
Keiko
K
Division of Medicinal Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. maekawa@nihs.go.jp
Harakawa
Noriko
N
Yoshimura
Takuya
T
Kim
Su-Ryang
SR
Fujimura
Yoshiyuki
Y
Aohara
Fumika
F
Sai
Kimie
K
Katori
Noriko
N
Tohkin
Masahiro
M
Naito
Mikihiko
M
Hasegawa
Ryuichi
R
Okuda
Haruhiro
H
Sawada
Jun-ichi
J
Niwa
Takuro
T
Saito
Yoshiro
Y
D000483:Alleles; D000818:Animals; D000069059:Atorvastatin; D055162:Biocatalysis; D002166:Camptothecin / Q000031:analogs & derivatives / Q000378:metabolism; D002220:Carbamazepine / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D000077143:Docetaxel; D005202:Asia, Eastern; D006538:Heptanoic Acids / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D008874:Midazolam / Q000378:metabolism; D008958:Models, Molecular; D017239:Paclitaxel / Q000378:metabolism; D011758:Pyrroles / Q000378:metabolism; D018411:Spodoptera; D013379:Substrate Specificity; D043823:Taxoids / Q000378:metabolism; D016593:Terfenadine / Q000378:metabolism
D006538:Heptanoic Acids; D011758:Pyrroles; D043823:Taxoids; D000077143:Docetaxel; D002220:Carbamazepine; D000077146:Irinotecan; D016593:Terfenadine; D000069059:Atorvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017239:Paclitaxel; D008874:Midazolam; D002166:Camptothecin