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http://dx.doi.org/10.4062/biomolther.2011.19.3.364

Effects of Curcumin on the Pharmacokinetics of Loratadine in Rats: Possible Role of CYP3A4 and P-glycoprotein Inhibition by Curcumin  

Li, Cheng (College of Pharmacy, Chosun University)
Choi, Byung-Chul (Health Insurance Review and Assessment Service)
Kim, Dong-Ki (College of Dentistry, Chosun University)
Choi, Jun-Shik (College of Pharmacy, Chosun University)
Publication Information
Biomolecules & Therapeutics / v.19, no.3, 2011 , pp. 364-370 More about this Journal
Abstract
The purpose of this study was to investigate the effects of curcumin on the pharmacokinetics of loratadine in rats. The effect of curcumin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was evaluated. Pharmacokinetic parameters of loratadine were also determined after oral and intravenous administration in the presence or absence of curcumin. Curcumin inhibited CYP3A4 activity with an IC50 value of 2.71 ${\mu}M$ and the relative cellular uptake of rhodamine-123 was comparable. Compared to the oral control group, curcumin significantly increased the area under the plasma concentration-time curve and the peak plasma concentration by 39.4-66.7% and 34.2-61.5%. Curcumin also significantly increased the absolute bioavailability of loratadine by 40.0-66.1% compared to the oral control group. Consequently, the relative bioavailability of loratadine was increased by 1.39- to 1.67-fold. In contrast, curcumin had no effect on any pharmacokinetic parameters of loratadine given intravenously, implying that the enhanced oral bioavailability may be mainly due to increased intestinal absorption caused via P-gp and CYP3A4 inhibition by curcumin rather than to reduced renal and hepatic elimination of loratadine. Curcumin enhanced the oral bioavailability of loratadine in this study. The enhanced bioavailability of loratadine might be mainly attributed to enhanced absorption in the gastrointestinal tract via the inhibition of P-gp and reduced fi rst-pass metabolism of loratadine via the inhibition of the CYP3A subfamily in the small intestine and/or in the liver by curcumin.
Keywords
Loratadine; Curcumin; Pharmacokinetics; CYP3A4; P-gp; Rats;
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1 Yumibe, N., Huie, K., Chen, K. J., Snow, M., Clement, R. P. and Cayen, M. N. (1996). Identifi cation of human liver cytochrome P450 enzymes that metabolize the nonsedating antihistamine loratadine. Formation of descarboethoxyloratadine by CYP3A4 and CYP2D6. Biochem. Pharmacol. 51, 165-172.   DOI
2 Srivastava, K. C., Bordia, A. and Verma, S. K. (1995). Curcumin, a major component of food spice turmeric (Curcuma longa) inhibits aggregation and alters eicosanoid metabolism in human blood platelets. Prostaglandins. Leukot. Essent. Fatty Acids. 52, 223-227.   DOI
3 Tanaka, T., Makita, H., Ohnishi, M., Hirose, Y., Wang, A., Mori, H., Satoh, K., Hara, A. and Ogawa, H. (1994). Chemoprevention of 4-nitroquinoline 1-oxide-induced oral carcinogenesis by dietary curcumin and hesperidin: comparison with the protective effect of beta-carotene. Cancer Res. 54, 4653-4659.
4 Tarnasky, P. R. and Van Arsdel, P. P. Jr. (1990). Antihistamine therapy in allergic rhinitis. J. Fam. Prac. 30, 71-80.
5 Thapliyal, R. and Maru, G. B. (2001). Inhibition of cytochrome P450 isozymes by curcumins in vitro and in vivo. Food Chem. Toxicol. 39, 541-547.   DOI
6 Wacher, V. J., Silverman, J. A., Zhang, Y. and 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.   DOI
7 Wang, E. J., Casciano, C. N., Clement, R. P. and Johnson, W. W. (2001). Evaluation of the interaction of loratadine and desloratadine with P-glycoprotein. Drug Metab. Dispos. 29, 1080-1083.
8 Wolozin, B., Kellman, W., Ruosseau, P., Celesia, G. G. and Siegel, G. (2000). Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch. Neurol. 10, 1439-1443.
9 Yin, O. Q., Shi, X. and Chow, M. S. (2003). Reliable and specifi c highperformance liquid chromatographic method for simultaneous determination of loratadine and its metabolite in human plasma. J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci. 796, 165-172.   DOI
10 Li, C., Kim, C. S., Yang, J. Y., Park, Y. J. and Choi, J. S. (2008). Effects of roxithromycin on the pharmacokinetics of loratadine after oral and intravenous administration of loratadine in rats. Eur. J. Drug Metab. Pharmacokinet. 33, 231-236.   DOI
11 Philpot, E. E. (2000). Safety of second generation antihistamines. Allerg. Asthma. Proc. 21, 15-19.   DOI
12 Pichard, L., Gillet, G., Fabre, I., Dalet-Beluche, I., Bonfi ls, C., Thenot, J. P. and Maurel, P. (1990). Identifi cation of the rabbit and human cytochromes P-450IIIA as the major enzymes involved in the Ndemethylation of diltiazem. Drug Metab. Dispos. 18, 711-719.
13 Shukla, P. K., Khanna, V. K., Ali, M. M. and Khan, M. Y. (2008). Anti-ischemic effect of curcumin in rat brain. Neurochem. Res. 33, 1036-1043.   DOI
14 Prenner, B. M., Capano, D. and Harris, A. G. (2000). Efficacy and tolerability of loratadine versus fexofenadine in the treatment of seasonal allergic rhinitis: adouble-blind comparison with crossover treatment of nonresponders. Clin. Ther. 22, 760-769.   DOI
15 Ramaekers, J. G., Uiterwijk, M. M. and O'Hanlon, J. F. (1992). Effects of loratadine and cetirizine on actual driving and psychometric test performance, and EEG during driving. Eur. J. Clin. Pharmacol. 42, 363-369.
16 Rao, C. V., Rivenson, A., Simi, B. and Reddy, B. S. (1995). Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound. Cancer Res. 55, 259-266.
17 Singh, S. V., Hu, X., Srivastava, S. K., Singh, M., Xia, H., Orchard, J. L. and Zaren, H. A. (1998). Mechanism of inhibition of benzo[a] pyrene-induced forestomach cancer in mice by dietary curcumin. Carcinogenesis 19, 1357-1360.   DOI
18 Singletary, K., MacDonald, C., Iovinelli, M., Fisher, C. and Wallig, M. (1998). Effect of the beta-diketones diferuloylmethane (curcumin) and dibenzoylmethane on rat mammary DNA adducts and tumors induced by 7,12-dimethylbenz[a]anthracene. Carcinogenesis 19, 1039-1043.   DOI
19 Govindarajan, V. S. (1980). Turmeric--chemistry, technology, and quality. Crit. Rev. Food Sci. Nutr. 12, 199-301.   DOI
20 Han, C. Y., Cho, K. B., Choi, H. S., Han, H. K. and Kang, K. W. (2008). Role of FoxO1 activation in MDR1 expression in adriamycin-resistant breast cancer cells. Carcinogenesis 29, 1837-1844.   DOI
21 Ito, K., Kusuhara, H. and Sugiyama, Y. (1999). Effects of intestinal CYP3A4 and P-glycoprotein on oral drug absorption; theoretical approach. Pharm. Res. 16, 225-231.   DOI
22 Hilbert, J., Radwanski, E., Weglein, R., Luc, V., Perentesis, G., Symchowicz, S. and Zampaglione, N. (1987). Pharmacokinetics and dose proportionality of loratadine. J. Clin. Pharmacol. 27, 694-698.   DOI
23 Huang, M. T., Lou, Y. R., Ma, W., Newmark, H. L., Reuhl, K. R. and Conney, A. H. (1994). Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon carcinogenesis in mice. Cancer Res. 54, 5841-5847.
24 Huang, M. T., Newmark, H. L. and Frenkel, K. (1997). Inhibitory effects of curcumin on tumorigenesis in mice. J. Cell Biochem. 27, 26-34.
25 Kaminsky, L. S. and Fasco, M. J. (1991). Small intestinal cytochromes P450. Crit. Rev. Toxicol. 21, 407-422.
26 Kay, G. G., Berman, B., Mockoviak, S. H., Morris, C. E., Reeves, D., Starbuck, V., Sukenik, E. and Harris, A. G. (1997). Initial and steady-state effects of diphenhydramine and loratadine on sedation, cognition, mood, and psychomotor performance. Arch. Intern. Med. 57, 2350-2356.
27 Kelly, P. A., Wang, H., Napoli, K. L., Kahan, B. D. and Strobel, H. W. (1999). Metabolism of cyclosporine by cytochromes P450 3A9 and 3A4. Eur. J. Drug. Metab. Pharmacokinet. 24, 321-328.   DOI
28 Kosoglou, T., Salfi , M., Lim, J. M., Batra, V. K., Cayen, M. N. and Affrime, M. B. (2000). Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine. Br. J. Clin. Pharmacol. 50, 581-589.
29 Cao, X., Gibbs, S. T., Fang, L., Miller, H. A., Landowski, C. P., Shin, H. C., Lennernas, H., Zhong, Y., Amidon, G. L., Yu, L. X. and Sun, D. (2006). Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model. Pharm. Res. 23, 1675-1686.   DOI
30 Carr, R. A., Edmonds, A., Shi, H., Locke, C. S., Gustavson, L. E., Craft, J. C., Harris, S. I. and Palmer, R. (1998). Steady-State Pharmacokinetics and Electrocardiographic Pharmacodynamics of Clarithromycin and Loratadine after Individual or Concomitant Administration. Antimicrob. Agents. Chemother. 42, 1176-1180.
31 Choi, H., Chun, Y. S., Kim, S. W., Kim, M. S. and Park, J. W. (2006). Curcumin inhibits hypoxia-inducible factor-1 by degrading aryl hydrocarbon receptor nuclear translocator: a mechanism of tumor growth inhibition. Mol. Pharm. 70, 1664-1671.   DOI
32 Clissold, S. P., Sorkin, E. M. and Goa, K. L. (1989). Loratadine, a preliminary review of its pharmacodynamic properties and therapeutic effi cacy. Drugs 37, 42-57.
33 Crespi, C. L., Miller, V. P. and Penman, B. W. (1997). Microtiter plate assays for inhibition of human, drug-metabolizing cytochromes P450. Anal. Biochem. 248, 188-190.   DOI
34 Cummins, C. L., Jacobsen, W. and Benet, L. Z. (2002). Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4. J. Pharmacol. Exp. Ther. 300, 1036-1045.   DOI
35 Deshpande, S. S., Ingle, A. D. and Maru, G. B. (1998). Chemopreventive effi cacy of curcumin-free aqueous turmeric extract in 7, 12-dimethylbenz [a] anthracene-induced rat mammary tumorigenesis. Cancer Lett. 123, 35-40.   DOI   ScienceOn
36 Efferth, T., Davey, M., Olbrich, A., Rücker, G., Gebhart, E. and Davey, R. (2002). Activity of drugs from traditional Chinese medicine toward sensitive and MDR1- or MRP1-overexpressing multidrugresistant human CCRF-CEM leukemia cells. Blood Cells Mol. Dis. 28, 160-168.   DOI
37 Bradley, C. M. and Nicholson, A. N. (1987). Studies on the central effects of the H1-antagonist, loratadine. Eur. J. Clin. Pharmacol. 32, 419-421.   DOI
38 Aggarwal, B. B. and Shishodia, S. (2006). Molecular targets of dietary agents for prevention and therapy of cancer. Biochem. Pharm. 71, 1397-1421.   DOI
39 Amini, H. and Ahmadiani, A. (2004). Rapid determination of loratadine in small volume plasma samples by high-performance liquid chromatography with fl uorescence detection. J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci. 809, 227-230.   DOI
40 Appiah-Opong, R., de Esch, I., Commandeur, J. N., Andarini, M. and Vermeulen, N. P. (2008). Structure-activity relationships for the inhibition of recombinant human cytochromes P450 by curcumin analogues. Eur. J. Med. Chem. 43, 1621-1631.   DOI