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Pharmacokinetics and pharmacodynamics of etizolam are influenced by polymorphic CYP2C19 activity

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

To examine the effect of cytochrome P450 (CYP) 2C19 activity on the single-dose pharmacokinetics and pharmacodynamics of etizolam.

Methods

The subjects were 21 healthy Japanese volunteers. The two mutated alleles (CYP2C19*2 and CYP2C19*3) causing absent CYP2C19 activity were identified by a polymerase chain reaction method. Twelve subjects were extensive metabolizers (EMs) with no or one mutated allele, and nine subjects were poor metabolizers (PMs) with two mutated alleles. The subjects received a single oral 1–mg dose of etizolam, and blood samplings and evaluation of psychomotor function were conducted up to 24 h after dosing.

Results

The PMs had significantly larger total area under the plasma concentration–time curve (287±74 vs 178±122 ng·h/ml, p<0.05) and longer elimination half–life (14.8±4.2 vs 10.5±3.9 h, p<0.05) of etizolam than the EMs. The area under the score–time curve from 0 to 8 h of the Stanford Sleepiness Scale was significantly larger in the PMs than in EMs (28.9±5.2 vs 22.9±6.9 score·h, p<0.05).

Conclusion

The present study suggests that the single-dose pharmacokinetics and pharmacodynamics of etizolam are influenced by polymorphic CYP2C19 activity.

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References

  1. Aoshima T, Fukasawa T, Otsuji Y, Okuyama N, Gerstenberg G, Miura M, Ohkubo T, Sugawara K, Otani K (2003) Effects of the CYP2C19 genotype and cigarette smoking on the single oral dose pharmacokinetics and pharmacodynamics of estazolam. Prog Neuropsychopharmacol Biol Psychiatry 27:535–538

    Article  PubMed  CAS  Google Scholar 

  2. Araki K, Yasui–Furukori N, Fukasawa T, Aoshima T, Suzuki A, Inoue Y, Tateishi T, Otani K (2004) Inhibition of the metabolism of etizolam by itraconazole in humans: evidence for the involvement of CYP3A4 in etizolam metabolism. Eur J Clin Pharmacol 60:427–430

    Article  PubMed  CAS  Google Scholar 

  3. Backman JT, Olkkola KT, Ojala M, Laaksovirta H, Neuvonen PJ (1996) Concentrations and effects of oral midazolam are greatly reduced in patients treated with carbamazepine or phenytoin. Epilepsia 37:253–257

    Article  PubMed  CAS  Google Scholar 

  4. Bertilsson L, Henthorn TK, Sanz E, Tybring G, Sawe J, Villen T (1989) Importance of genetic factors in the regulation of diazepam metabolism: relationship to S–mephenytoin, but not debrisoquin, hydroxylation phenotype. Clin Pharmacol Ther 45:348–355

    Article  PubMed  CAS  Google Scholar 

  5. Casacchia M, Bolino F, Ecari U (1990) Etizolam in the treatment of generalized anxiety disorder: a double–bind study versus placebo. Curr Med Res Opin 12:215–223

    PubMed  CAS  Google Scholar 

  6. de Morais SM, Goldstein JA, Xie HG, Huang SL, Lu YQ, Xia H, Xiao ZS, Ile N, Zhou HH (1995) Genetic analysis of the S–mephenytoin polymorphism in a Chinese population. Clin Pharmacol Ther 58:404–411

    Article  PubMed  CAS  Google Scholar 

  7. Fukasawa T, Yasui–Furukori N, Aoshima T, Suzuki A, Tateishi T, Otani K (2004) Single oral dose pharmacokinetics of quazepam is influenced by CYP2C19 activity. Ther Drug Monit 26:529–533

    Article  PubMed  CAS  Google Scholar 

  8. Furukori H, Otani K, Yasui N, Kondo T, Kaneko S, Shimoyama R, Ohkubo T, Nagasaki T, Sugawara K (1998) Effect of carbamazepine on the single oral dose pharmacokinetics of alprazolam. Neuropsychopharmacology 18:364–369

    Article  PubMed  CAS  Google Scholar 

  9. Gafni I, Busto UE, Tyndale EF, Kaplan HL, Sellers EM (2003) The role of cytochrome P450 2C19 activity in flunitrazepam metabolism in vivo. J Clin Psychopharmacol 23:169–175

    Article  PubMed  CAS  Google Scholar 

  10. Goldstein JA, Blaisdell J (1996) Genetic tests which identify the principal defects in CYP2C19 responsible for the polymorphism in mephenytoin metabolism. Methods Enzymol 272:210–218

    Article  PubMed  CAS  Google Scholar 

  11. Goldstein JA, de Morais SMF (1994) Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics 4:285–299

    Article  PubMed  CAS  Google Scholar 

  12. Hikida K, Inoue Y, Nouchi E, Ohkura Y (1990) Determination of etizolam in human serum or plasma using automated column–switching high–performance liquid chromatography. Jpn J Clin Chem 19:354–359

    CAS  Google Scholar 

  13. Hoddes E, Zarcone V, Smythe H, Phillips R, Dement WC (1973) Quantification of sleepiness: a new approach. Psychophysiology 10:413–416

    Article  Google Scholar 

  14. Kondo S, Fukasawa T, Yasui–Furukori N, Aoshima T, Suzuki A, Inoue Y, Tateishi T, Otani K (2005) Induction of the metabolism of etizolam by carbamazepine in humans. Eur J Clin Pharmacol 63:185–188

    Article  CAS  Google Scholar 

  15. Kubota T, Chiba K, Ishizaki T (1996) Genotyping of S–mephenytoin 4'–hydroxylation in an extended Japanese population. Clin Pharmacol Ther 60:661–666

    Article  PubMed  CAS  Google Scholar 

  16. Mitsubishi Pharma (2003) Unpublished data in package insert

  17. Nakajima M, Yokoi T, Mizutani M, Kinoshita M, Funayama M, Kamataki T (1999) Genetic polymorphism in the 5'–flanking region of human CYP1A2 gene: effect on the CYP1A2 inducibility in humans. J Biochem 125:803–808

    PubMed  CAS  Google Scholar 

  18. Olkkola KT, Backman JT, Neuvonen PJ (1994) Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 55:481–485

    Article  PubMed  CAS  Google Scholar 

  19. Otani K, Yasui N, Kaneko S, Ohkubo T, Osanai T, Sugawara K, Hayashi K, Chiba K, Ishizaki T (1997) Effects of genetically determined S–mephenytoin 4–hydroxylation status and cigarette smoking on the single–dose pharmacokinetics of oral alprazolam. Neuropsychopharmacology 16:8–14

    Article  PubMed  CAS  Google Scholar 

  20. Qin XP, Xie HG, Wang W, He N, Huang SL, Xu ZH, Ou–Yang DS, Wang YJ, Zhou HH (1999) Effect of the gene dosage of CYP2C19 on diazepam metabolism in Chinese subjects. Clin Pharmacol Ther 66:642–646

    PubMed  CAS  Google Scholar 

  21. Savoldi F, Somenzini G, Ecari U (1990) Etizolam versus placebo in the treatment of panic disorder with agoraphobia: a double–blind study. Curr Med Res Opin 12:185–190

    PubMed  CAS  Google Scholar 

  22. Tsumagari T, Nakajima A, Fukuda T, Shuto S, Kenjo T, Morimoto Y, Takigawa Y (1978) Pharmacological properties of 6–(o–chrorophenyl)–8–ethyl–1–methyl–4H–s–triazolo[3,4–c]thieno[2,3–e][1,4]diazepine(Y–7131), a new anti–anxiety drug. Arzneimittelforschung 28:1158–1178

    Google Scholar 

  23. Varhe A, Olkkola KT, Neuvonen PJ (1994) Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 56:601–607

    Article  PubMed  CAS  Google Scholar 

  24. Venkatakrishnan K, Greenblatt DJ, von Moltke LL, Shader RI (1998) Alprazolam is another substrate for human cytochrome P450–3A isoforms. J Clin Psychopharmacol 18:256

    Article  PubMed  CAS  Google Scholar 

  25. Yasui N, Otani K, Ohkubo T, Osanai T, Sugawara K, Chiba K, Ishizaki T, Kaneko S (1997) Single–dose pharmacokinetics and pharmacodynamics of oral triazolam in relation to cytochrome P4502C19 (CYP2C19) activity. Ther Drug Monit 19:371–374

    Article  PubMed  CAS  Google Scholar 

  26. Yasui N, Kondo T, Otani K, Furukori H, Kaneko S, Ohkubo T, Osanai T, Nagasaki T, Sugawara K (1998) Effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam. Psychopharmacology 139:269–273

    Article  PubMed  CAS  Google Scholar 

  27. Wechsler D (1981) Wechsler Adult Intelligence Scale–Revised. Harcourt Brace Jovanovich, New York, NY

    Google Scholar 

  28. Zar JH (1999) Biostatistical analysis, 4th edn. Prentice–Hall, Upper Saddle River, NJ

    Google Scholar 

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Authors and Affiliations

  1. Department of Psychiatry, Yamagata University School of Medicine, 990-9585, Yamagata, Japan

    T. Fukasawa, A. Suzuki & K. Otani

  2. Department of Clinical Pharmacology, Hirosaki University School of Medicine, Hirosaki, Japan

    N. Yasui–Furukori & T. Tateishi

  3. Technology Department, MP–Technopharma Corporation, Fukuoka, Japan

    Y. Inoue

Authors
  1. T. Fukasawa
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  2. N. Yasui–Furukori
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  3. A. Suzuki
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  4. Y. Inoue
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  5. T. Tateishi
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  6. K. Otani
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Corresponding author

Correspondence to T. Fukasawa.

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Fukasawa, T., Yasui–Furukori, N., Suzuki, A. et al. Pharmacokinetics and pharmacodynamics of etizolam are influenced by polymorphic CYP2C19 activity. Eur J Clin Pharmacol 61, 791–795 (2005). https://doi.org/10.1007/s00228-005-0032-8

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  • DOI: https://doi.org/10.1007/s00228-005-0032-8

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