Distinct Inhibitory Effects of Tacrolimus and Cyclosporin A on Calcineurin Phosphatase Activity

  1. Masahide Fukudo,
  2. Ikuko Yano,
  3. Satohiro Masuda,
  4. Masahiro Okuda and
  5. Ken-ichi Inui
  1. Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan
  1. Address correspondence to:
    Dr. Ken-ichi Inui, Department of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: inui{at}kuhp.kyoto-u.ac.jp

Abstract

We have compared the pharmacodynamic properties of calcineurin inhibitors tacrolimus and cyclosporin A in rats to clarify the different therapeutic drug monitoring strategy of both drugs in a clinical situation. In various tissue extracts, the inhibition of calcineurin activity by cyclosporin A was significantly greater than that by tacrolimus at the same drug concentration (1 μM) in the thymus, heart, liver, spleen, kidney, and testis (p < 0.05). The time profiles of blood concentrations and calcineurin activity in whole blood were examined after single or repeated administration of each drug in rats. A substantial time delay in the inhibition was observed following the single administration of tacrolimus or cyclosporin A, resulting in an anticlockwise hysteresis in the relationship between blood concentrations and calcineurin inhibition in whole blood. In contrast, such a hysteresis loop diminished after the repeated administration of each drug, and the recovery rate of calcineurin activity was greater for the inhibition induced by cyclosporin A than by tacrolimus. Furthermore, tacrolimus produced a comparable inhibition of calcineurin activity in whole blood at lower blood concentrations than cyclosporin A. Overall, the effect compartment model well described the time profiles of calcineurin activity in whole blood after the single and repeated administrations of each drug. These findings suggest that the properties of calcineurin inhibition differ between tacrolimus and cyclosporin A. Distinct pharmacodynamics may partly contribute to the therapeutic drug monitoring strategy in transplant patients receiving calcineurin inhibitors.

Footnotes

  • This project was supported in part by the 21st Century Center of Excellence Program “Knowledge Information Infrastructure for Genome Science”, by a grant-in-aid from the Japan Health Sciences Foundation, by a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by Novartis Ciclosporin Pharmaco-Clinical Forum Research Grant 2004. Masahide Fukudo is a Research Fellow of the Japan Society for the Promotion of Science.

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

  • doi:10.1124/jpet.104.074930.

  • ABBREVIATIONS: AUC0–24 h, area under the concentration-time curve over 24 h; AUE0–96 h, incremental area under the pharmacodynamic effect-time curve over 96 h.

    • Received July 24, 2004.
    • Accepted September 21, 2004.
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  1. Published online before print September 21, 2004, doi: 10.1124/jpet.104.074930 JPET February 2005 vol. 312 no. 2 816-825
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