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Research ArticleArticle

AUTOINDUCTION OF MKC-963 [(R)-1-(1-CYCLOHEXYLETHYLAMINO)-4-PHENYLPHTHALAZINE] METABOLISM IN HEALTHY VOLUNTEERS AND ITS RETROSPECTIVE EVALUATION USING PRIMARY HUMAN HEPATOCYTES AND CDNA-EXPRESSED ENZYMES

Toshiyuki Shimizu, Kei Akimoto, Takuya Yoshimura, Takuro Niwa, Kaoru Kobayashi, Michio Tsunoo and Kan Chiba
Drug Metabolism and Disposition June 2006, 34 (6) 950-954; DOI: https://doi.org/10.1124/dmd.105.007997
Toshiyuki Shimizu
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Kei Akimoto
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Takuya Yoshimura
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Takuro Niwa
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Kaoru Kobayashi
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Michio Tsunoo
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Kan Chiba
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Abstract

MKC-963, (R)-1-(1-cyclohexylethylamino)-4-phenylphthalazine, a potent inhibitor of platelet aggregation, was synthesized and used in clinical trials in the 1990s. In the process of clinical study, it was found that urinary excretion ratios for 6β-hydroxycortisol and free cortisol increased significantly in parallel with decreases in the plasma concentrations of MKC-963 after repeated oral administration of the compound to healthy volunteers. These findings suggested that MKC-963 caused autoinduction (defined as the ability of a drug to induce enzymes that enhance its own metabolism, resulting in dispositional tolerance) in humans, and clinical studies using the compound were stopped. This experience prompted us to reevaluate the effects of this compound on CYP3A4 using primary human hepatocytes and cDNA-expressed human cytochrome P450 (P450) enzymes to determine whether the autoinduction of MKC-963 metabolism in humans could have been predicted if these in vitro systems had been used for the evaluation of MKC-963 in the preclinical study. The results of in vitro study showed that MKC-963 increased CYP3A4 mRNA expression level and activity of testosterone 6β-hydroxylation to extents similar to those observed with rifampicin in primary human hepatocytes. In addition, approximately 90% of the MKC-963 metabolism in human liver microsomes was estimated to be attributable to CYP3A4. These in vitro findings are in good agreement with the results of clinical study, suggesting that studies using human hepatocytes and cDNA-expressed human P450s are useful for assessing the autoinductive nature of compounds under development before starting clinical studies.

Footnotes

  • ↵1 Autoinduction is defined as the ability of a drug to induce enzymes that enhance its own metabolism, resulting in dispositional tolerance.

  • This work was supported in part by Cooperative Study of Mitsubishi Pharma Corporation and Chiba University, a grant-in-aid from the Ministry of Health, Labor and Welfare of Japan (Research on Regulatory Science of Pharmaceutical and Medical Devices), and Research on Health Sciences focusing on Drug Innovation from The Japan Health Sciences Foundation (KH71069 and KH33309).

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

  • doi:10.1124/dmd.105.007997.

  • ABBREVIATIONS: MKC-963, (R)-1-(1-cyclohexylethylamino)-4-phenylphthalazine; d5MKC-963, MKC-963 with 5 hydrogen substituted by deuterium in the phenyl ring; MGB, minor groove binder; AUC, area under the plasma concentration-time curve; Cmax, maximum plasma concentration; tmax, time to reach Cmax; t1/2, terminal half-life; F, cortisol; 6β-OHF, 6β-hydroxycortisol; P450, cytochrome P450; CL, in vitro clearance.

    • Received October 25, 2005.
    • Accepted March 3, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (6)
Drug Metabolism and Disposition
Vol. 34, Issue 6
1 Jun 2006
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AUTOINDUCTION OF MKC-963 [(R)-1-(1-CYCLOHEXYLETHYLAMINO)-4-PHENYLPHTHALAZINE] METABOLISM IN HEALTHY VOLUNTEERS AND ITS RETROSPECTIVE EVALUATION USING PRIMARY HUMAN HEPATOCYTES AND CDNA-EXPRESSED ENZYMES
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Research ArticleArticle

AUTOINDUCTION OF MKC-963 [(R)-1-(1-CYCLOHEXYLETHYLAMINO)-4-PHENYLPHTHALAZINE] METABOLISM IN HEALTHY VOLUNTEERS AND ITS RETROSPECTIVE EVALUATION USING PRIMARY HUMAN HEPATOCYTES AND CDNA-EXPRESSED ENZYMES

Toshiyuki Shimizu, Kei Akimoto, Takuya Yoshimura, Takuro Niwa, Kaoru Kobayashi, Michio Tsunoo and Kan Chiba
Drug Metabolism and Disposition June 1, 2006, 34 (6) 950-954; DOI: https://doi.org/10.1124/dmd.105.007997

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Research ArticleArticle

AUTOINDUCTION OF MKC-963 [(R)-1-(1-CYCLOHEXYLETHYLAMINO)-4-PHENYLPHTHALAZINE] METABOLISM IN HEALTHY VOLUNTEERS AND ITS RETROSPECTIVE EVALUATION USING PRIMARY HUMAN HEPATOCYTES AND CDNA-EXPRESSED ENZYMES

Toshiyuki Shimizu, Kei Akimoto, Takuya Yoshimura, Takuro Niwa, Kaoru Kobayashi, Michio Tsunoo and Kan Chiba
Drug Metabolism and Disposition June 1, 2006, 34 (6) 950-954; DOI: https://doi.org/10.1124/dmd.105.007997
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