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Rapid CommunicationShort Communication

CYP3A4*16 and CYP3A4*18 Alleles Found in East Asians Exhibit Differential Catalytic Activities for Seven CYP3A4 Substrate Drugs

Keiko Maekawa, Noriko Harakawa, Takuya Yoshimura, Su-Ryang Kim, Yoshiyuki Fujimura, Fumika Aohara, Kimie Sai, Noriko Katori, Masahiro Tohkin, Mikihiko Naito, Ryuichi Hasegawa, Haruhiro Okuda, Jun-ichi Sawada, Takuro Niwa and Yoshiro Saito
Drug Metabolism and Disposition December 2010, 38 (12) 2100-2104; DOI: https://doi.org/10.1124/dmd.110.034140
Keiko Maekawa
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Noriko Harakawa
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Takuya Yoshimura
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Su-Ryang Kim
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Yoshiyuki Fujimura
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Fumika Aohara
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Kimie Sai
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Noriko Katori
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Masahiro Tohkin
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Mikihiko Naito
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Ryuichi Hasegawa
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Haruhiro Okuda
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Jun-ichi Sawada
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Takuro Niwa
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Yoshiro Saito
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Abstract

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 (Vmax/Km) that were lowered considerably (by 84–60%) for metabolism of midazolam, carbamazepine, atorvastatin, paclitaxel, and irinotecan compared with CYP3A4.1 due to increased Km with or without decreased Vmax values, whereas no apparent decrease in intrinsic clearance was observed for docetaxel. On the other hand, Km values for CYP3A4.18 were comparable to those for CYP3A4.1 for all substrates except terfenadine; but Vmax 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.

Footnotes

  • This study was supported in part by the Program for the Promotion of Fundamental Studies in Health Sciences; and the Health and Labor Sciences Research Grants from the Ministry of Health, Labor and Welfare.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.034140.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    APC
    7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin
    TST
    testosterone
    MDZ
    midazolam
    CBZ
    carbamazepine
    1′-OH-MDZ
    1′-hydroxymidazolam
    ATV
    atorvastatin
    PTX
    paclitaxel
    DTX
    docetaxel
    IRN
    irinotecan
    TFN
    terfenadine
    4-OH-MDZ
    4-hydroxymidazolam
    3′-p-OH-PTX
    3′-p-hydroxypaclitaxel
    2-OH-ATV
    2-hydroxyatorvastatin
    4-OH-ATV
    4-hydroxyatorvastatin
    NPC
    7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin
    OR
    NADPH P450 reductase.

  • Received April 28, 2010.
  • Accepted September 16, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (12)
Drug Metabolism and Disposition
Vol. 38, Issue 12
1 Dec 2010
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Rapid CommunicationShort Communication

CYP3A4*16 and CYP3A4*18 Alleles Found in East Asians Exhibit Differential Catalytic Activities for Seven CYP3A4 Substrate Drugs

Keiko Maekawa, Noriko Harakawa, Takuya Yoshimura, Su-Ryang Kim, Yoshiyuki Fujimura, Fumika Aohara, Kimie Sai, Noriko Katori, Masahiro Tohkin, Mikihiko Naito, Ryuichi Hasegawa, Haruhiro Okuda, Jun-ichi Sawada, Takuro Niwa and Yoshiro Saito
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2100-2104; DOI: https://doi.org/10.1124/dmd.110.034140

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Rapid CommunicationShort Communication

CYP3A4*16 and CYP3A4*18 Alleles Found in East Asians Exhibit Differential Catalytic Activities for Seven CYP3A4 Substrate Drugs

Keiko Maekawa, Noriko Harakawa, Takuya Yoshimura, Su-Ryang Kim, Yoshiyuki Fujimura, Fumika Aohara, Kimie Sai, Noriko Katori, Masahiro Tohkin, Mikihiko Naito, Ryuichi Hasegawa, Haruhiro Okuda, Jun-ichi Sawada, Takuro Niwa and Yoshiro Saito
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2100-2104; DOI: https://doi.org/10.1124/dmd.110.034140
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