QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.074930v1 312/2/816    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fukudo, M. Articles by Inui, K.-i. Search for Related Content PubMed PubMed Citation Articles by Fukudo, M. Articles by Inui, K.-i.

INFLAMMATION AND IMMUNOPHARMACOLOGY

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

Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan

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.

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

This article has been cited by other articles:

				M. Goto, S. Masuda, T. Kiuchi, Y. Ogura, F. Oike, K. Tanaka, S. Uemoto, and K.-i. Inui Relation between mRNA Expression Level of Multidrug Resistance 1/ABCB1 in Blood Cells and Required Level of Tacrolimus in Pediatric Living-Donor Liver Transplantation J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 610 - 616. [Abstract] [Full Text] [PDF]

				H. H. van Rossum, F. P.H.T.M. Romijn, K. J. Sellar, N. P.M. Smit, P. J.M. van der Boog, J. W. de Fijter, and J. van Pelt Variation in Leukocyte Subset Concentrations Affects Calcineurin Activity Measurement: Implications for Pharmacodynamic Monitoring Strategies Clin. Chem., March 1, 2008; 54(3): 517 - 524. [Abstract] [Full Text] [PDF]