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Evidence-Based Complementary and Alternative Medicine
Volume 2011, Article ID 751671, 6 pages
Research Article

Different Influences on Tacrolimus Pharmacokinetics by Coadministrations of Zhi Ke and Zhi Shi in Rats

1School of Pharmacy, China Medical University, Taichung 40402, Taiwan
2School of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung 40402, Taiwan
3Institute of Athletics, National Taiwan College of Physical Education, Taichung 40404, Taiwan

Received 12 July 2010; Revised 19 October 2010; Accepted 28 December 2010

Copyright © 2011 Shiuan-Pey Lin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Tacrolimus, an immunosuppressant with narrow therapeutic window, has been used widely in transplant patients. Grapefruit juice and pomelo have been reported to increase the blood levels of tacrolimus. Zhi Ke and Zhi Shi, the ripe peels and unripe fruits of Citrus aurantium which is chemotaxonomically related to grapefruit and pomelo, are in wide use in clinical Chinese medicine. To investigate the possible interaction of these two Citrus herbs with tacrolimus, male Sprague-Dawley rats were orally given tacrolimus (1.5 mg/kg) with and without Zhi Ke and Zhi Shi decoctions in a cross-over design. Blood samples were withdrawn via cardiopuncture at specific time and quantitated by a microparticle enzyme immunoassay. In addition, to explore the mechanism of interaction, LS 180 cell line was used for the transport study of rhodamine 123, a typical substrate of P-glycoprotein (P-gp). The results showed that Zhi Shi significantly decreased the Cmax and AUC0-t of tacrolimus by 72.4% and 72.0%, respectively, whereas Zhi Ke did not affect tacrolimus pharmacokinetics. LS 180 cell line study indicated that Zhi Shi increased the efflux activity of P-gp, enabling us to explain the decreased oral bioavailability of tacrolimus caused by Zhi Shi. Hence, we suggest that Zhi Shi be contraindicated for transplant patients treated with tacrolimus to reduce the risk of allograft rejection.