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Rapid CommunicationShort Communication

Human Buprenorphine N-Dealkylation Is Catalyzed by Cytochrome P450 3A4

Kaoru Kobayashi, Toshinori Yamamoto, Kan Chiba, Masayoshi Tani, Noriaki Shimada, Takashi Ishizaki and Yukio Kuroiwa
Drug Metabolism and Disposition August 1998, 26 (8) 818-821;
Kaoru Kobayashi
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Toshinori Yamamoto
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Kan Chiba
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Masayoshi Tani
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Noriaki Shimada
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Takashi Ishizaki
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Abstract

Buprenorphine (BN) is a thebaine derivative with analgesic properties. To identify and characterize the cytochrome P450 (CYP) enzyme(s) involved in BN N-dealkylation, in vitro studies using human liver microsomes and recombinant human CYP enzymes were performed. Norbuprenorphine formation from BN was measured by a simple HPLC-UV assay method, without extraction. The BNN-dealkylation activities in 10 human liver microsomal preparations were strongly correlated with microsomal CYP3A-specific metabolic reactions, i.e. triazolam 1′-hydroxylation (r = 0.954), midazolam 1′-hydroxylation (r = 0.928), and testosterone 6β-hydroxylation (r = 0.897). Among the eight recombinant CYP enzymes studied (CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4), only CYP3A4 could catalyze BN N-dealkylation. The apparent KM value for recombinant CYP3A4 was similar to that for human liver microsomes (23.7 vs.39.3 ± 9.2 μM). The demonstration of BNN-dealkylation by recombinant CYP3A4 and the agreement in the affinities (apparent KM values) of human liver microsomes and recombinant CYP3A4 provide the most supportive evidence for BN N-dealkylation being catalyzed by CYP3A4.

Footnotes

  • Send reprint requests to: Prof. Toshinori Yamamoto, Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Showa University, Hatanodai 1–5-8, Shinagawa-ku, Tokyo 142, Japan.

  • This study was supported by a Grant-in-aid for Encouragement of Young Scientists from the Ministry of Education and Science (Grant 06772215), by the Japan Health Science Foundation (Grant 1–7-1-C), and by the Drug Innovation Science Project (Grant 1–2-10) (Tokyo, Japan).

  • Abbreviations used are::
    BN
    buprenorphine
    NBN
    norbuprenorphine
    CYP
    cytochrome P450
    • Received August 15, 1997.
    • Accepted March 14, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 26, Issue 8
1 Aug 1998
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Rapid CommunicationShort Communication

Human Buprenorphine N-Dealkylation Is Catalyzed by Cytochrome P450 3A4

Kaoru Kobayashi, Toshinori Yamamoto, Kan Chiba, Masayoshi Tani, Noriaki Shimada, Takashi Ishizaki and Yukio Kuroiwa
Drug Metabolism and Disposition August 1, 1998, 26 (8) 818-821;

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Rapid CommunicationShort Communication

Human Buprenorphine N-Dealkylation Is Catalyzed by Cytochrome P450 3A4

Kaoru Kobayashi, Toshinori Yamamoto, Kan Chiba, Masayoshi Tani, Noriaki Shimada, Takashi Ishizaki and Yukio Kuroiwa
Drug Metabolism and Disposition August 1, 1998, 26 (8) 818-821;
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