Advertisement

Pharmacokinetics of YK754, a novel If channel inhibitor in rats, dogs and humans

  • K-I. Umehara
  • T. Nakamata
  • K. Suzuki
  • K. Noguchi
  • T. Usui
  • H. Kamimura
Article

Summary

The pharmacokinetics of YM758, a novelfunny If current channel (If channel) inhibitor, was investigated after single intravenous (i.v.) and oral dosing to rats and dogs, and partially compared with the results in humans by using liver microsomes. After i.v. administration, the plasma YM758 concentrations decreased, with an elimination half-life (t1/2) of 1.14–1.16 h in rats and 1.10–1.30 h in dogs. Total body clearance (CLtot) was 5.71–7.27 and 1.75–1.90 L/h/kg in rats and dogs, respectively which was comparable to the hepatic blood flow rate. In dogs, the pharmacokinetic profiles for i.v. bolus administration and continuous infusion did not differ. After oral administration, the levels of YM758 in rat plasma increased more than dose-proportionally, whereas almost linear pharmacokinetics were observed in dogs. Absolute bioavailability was 7.5%–16.6% in rats and 16.1%–22.0% in dogs. The plasma protein binding saturation of YM758 was observed in dogs and humans; this finding is consistent with the result that the major binding protein of YM758 in plasma is α1-acid glycoprotein (AGP), in particular in humans. The blood-to-plasma partition coefficient values were 1.36–1.42 in rats, 0.95–1.15 in dogs and 0.71–0.85 in humans. The results of the metabolic study on liver microsomes indicated that the non-linear pharmacokinetics of YM758 observed in rats may be partially due to a first-pass effect in the gastrointestinal tract and the liver.

Key words

Pharmacokinetics If channel inhibitor plasma protein binding blood cell transfer first-pass effect 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Bucchi A., Barbuti A., Baruscotti M., DiFrancesco D. (2007): Heart rate reduction via selective ‘funny’ channel blockers. Curr. Opin. Pharmacol., 7, 208–213.CrossRefPubMedGoogle Scholar
  2. 2.
    Indolfi C, Guth B.D., Miura T., Miyazaki S., Schulz R., Ross J Jr. (1989): Mechanisms of improved ischemic regional dysfunction by bradycardia. Studies on UL-FS 49 in swine. Circulation, 80, 983–993.PubMedGoogle Scholar
  3. 3.
    Roth W., Bauer E., Heinzel G, Cornelissen P.J., van Toi R.G., Jonkman J.H., Zuiderwijk P.B. (1993): Zatebradine: pharmacokinetics of a novel heart-rate-lowering agent after i.v. infusion and oral administration to healthy subjects. J. Pharma. Sci., 82, 99–106.CrossRefGoogle Scholar
  4. 4.
    Umehara K.I., Seya K., Sonoda T., Nakamura E., Noguchi K., Usui T., Kamimura H. (2008): Comparative evaluation of absorption, distribution, and excretion of YM758, a novel If channel inhibitor, between albino and non-albino rats. Xenobiotica, 38, 527–539.CrossRefPubMedGoogle Scholar
  5. 5.
    Umehara K., Iwai M., Adachi Y., Usui T., Iwatsubo T., Kamimura H. (2008): Hepatic uptake and excretion of YM758, a novel If channel inhibitor, in rats and humans. Drug Metab. Pharmacokinet., 36, 1030–1038.Google Scholar
  6. 6.
    Leon S., Andrew Y. (1999): Applied Biopharmaceutics & Pharmacokinetics, 4th edn. CT, USA: Appleton & Lange.Google Scholar
  7. 7.
    Dedrick R.L., Zaharko D.S., Lutz R.J. (1973): Transport and binding of methotrexatein vivo. J. Pharm. Sci., 62, 882–890.CrossRefPubMedGoogle Scholar
  8. 8.
    Wacher V.J., Silverman J.A., Zhang Y., Benet L.Z. (1998): Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. J. Pharm. Sci., 87, 1322–1330.CrossRefPubMedGoogle Scholar
  9. 9.
    Greenway C.V., Stark R.D. (1971): Hepatic vascular bed. Physiol. Rev., 51, 23–65.PubMedGoogle Scholar
  10. 10.
    Iwatsubo T., Suzuki H., Sugiyama Y. (1997): Prediction of species differences (rats, dogs, humans) in thein vivo metabolic clearance of YM796 by the liver fromin vitro data. J. Pharmacol. Exp. Ther., 283, 462–469.PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • K-I. Umehara
    • 1
  • T. Nakamata
    • 2
  • K. Suzuki
    • 1
  • K. Noguchi
    • 1
  • T. Usui
    • 1
  • H. Kamimura
    • 1
  1. 1.Drug Metabolism Research Laboratories, Drug Discovery ResearchAstelias Pharma Inc.TokyoJapan
  2. 2.Pharmacokinetics and Bioanalysis CenterShin Nippon Biomedical Laboratories, Ltd.WakayamaJapan

Personalised recommendations