Browse > Article
http://dx.doi.org/10.4062/biomolther.2020.006

Effects of Diabetes Mellitus on the Disposition of Tofacitinib, a Janus Kinase Inhibitor, in Rats  

Gwak, Eun Hye (College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University)
Yoo, Hee Young (College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University)
Kim, So Hee (College of Pharmacy and Research Institute of Pharmaceutical Science and Technology, Ajou University)
Publication Information
Biomolecules & Therapeutics / v.28, no.4, 2020 , pp. 361-369 More about this Journal
Abstract
Tofacitinib, a Janus kinase inhibitor, was developed for the treatment of rheumatoid arthritis. Recently, it has been associated with an increased change in arthritis development in patients with diabetes. Herein, we evaluated the pharmacokinetics of tofacitinib after intravenous (10 mg/kg) and oral (20 mg/kg) administration to rats with streptozotocin-induced diabetes mellitus and control rats. Following intravenous administration of tofacitinib to rats with streptozotocin-induced diabetes mellitus, area under the plasma concentration-time curve from time zero to infinity of tofacitinib was significantly smaller (33.6%) than that of control rats. This might be due to the faster hepatic intrinsic clearance (112%) caused by an increase in the hepatic cytochrome P450 (CYP) 3A1(23) and the faster hepatic blood flow rate in rats with streptozotocin-induced diabetes mellitus than in control rats. Following oral administration, area under the plasma concentration-time curve from time zero to infinity of tofacitinib was also significantly smaller (55.5%) in rats with streptozotocin-induced diabetes mellitus than that in control rats. This might be due to decreased absorption caused by the higher expression of P-glycoprotein and the faster intestinal metabolism caused by the higher expression of intestinal CYP3A1(23), which resulted in the decreased bioavailability of tofacitinib (33.0%) in rats with streptozotocin-induced diabetes mellitus. In summary, our findings indicate that diabetes mellitus affects the absorption and metabolism of tofacitinib, causing faster metabolism and decreased intestinal absorption in rats with streptozotocin-induced diabetes mellitus.
Keywords
Tofacitinib; CYP3A1(23); Streptozotocin-induced diabetes mellitus; P-pg; Intrinsic clearance; Pharmacokinetics;
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
연도 인용수 순위
1 Molsted, S., Bjorkman, A. S. D., Andersen, M. B. and Ekholm, O. (2018) Diabets is associated with elevated risks of osteoarthritis, osteoporosis and rheumatoid arthritis. 54th Annual Meeting of the European Association for the Study of Diabetes (EASD). Abstract 1112, Oct. 1-5, 2018. Berlin, Germany.
2 Choi, Y. H., Lee, D. C. and Lee, M. G. (2008) Changes in metformin pharmacokinetics after intravenous and oral administration to rats with short-term and long-term diabetes induced by streptozotocin. J. Pharm. Sci. 97, 5363-5375.   DOI
3 Nadai, M., Yoshizumi, H., Kuzuya, T., Hasgawa, T., Johno, I. and Kitazawa, S. K. (1990) Effects of diabetes on disposition and renal handling of cefazolin in rats. J. Pharmacol. Exp. Ther. 18, 565-570.
4 Papp, K. A., Menter, M. A., Abe, M., Elewski, B., Feldman, S. R., Gottlieb, A. B., Langley, R., Luger, T., Thaci, D., Buonanno, M., Gupta, P., Proulx, J., Lan, S. and Wolk, R.; OPT Pivotal 1 and OPT Pivotal 2 investigators (2015) Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled, phase III trials. Br. J. Dermatol. 173, 949-961.   DOI
5 Park, J. M., Moon, C. H. and Lee, M. G. (1996) Pharmacokinetic changes of methotrexate after intravenous administration to streptozotocin-induced diabetes mellitus rats. Res. Commun. Mol. Pathol. Pharmacol. 93, 343-352.
6 Pickup, J. C. and Williams, G. (1991) Textbook of Diabetes. Blackwell Scientific Publications, Oxford.
7 Riese, R. J., Krishnaswami, S. and Kremer, J. (2010) Inhibition of JAK kinases in patients with rheumatoid arthritis: scientific rationale and clinical outcomes. Best Pract. Res. Clin. Rheumatol. 24, 5513-5526.
8 Sato, H., Terasaki, T., Okumura, K. and Tsuji, A. (1991) Effect of receptor-up-regulation on insulin pharmacokinetics in streptozotocintreated diabetic rats. Pharm. Res. 8, 563-569.   DOI
9 Shin, W. G., Lee, M. G., Lee, M. H. and Kim, N. D. (1991) Factors influencing the protein binding of vancomycin. Biopharm. Drug Dispos. 12, 637-646.   DOI
10 Claxton, L., Taylor, M., Soonasra, A., Bourret, J. A. and Gerber, R. A. (2018) An economic evaluation of tofacitinib treatment in rheumatoid arthritis after methotrexate or after 1 or 2 TNF inhibitors from a U.S. payer perspective. J. Manag. Care Spec. Pharm. 24, 1010-1017.   DOI
11 Coombs, J. H., Bloom, B. J. and Breedveld, F. C. (2010) Improved pain, physical functioning and health status in patients with rheumatoid arthritis treated with CP-690,550, an orally active Janus kinase (JAK) inhibitor: results from randomized, double-blind, placebo-controlled trial. Ann. Rheum. Dis. 69, 413-416.   DOI
12 Dowty, M. E., Lin, J., Ryder, T. F., Wang, W., Walker, G. S., Vaz, A., Chan, G. L., Krishnaswami, S. and Prakash, C. (2014) The pharmacokinetics, metabolism, and clearance mechanisms of tofacitinib, a janus kinase inhibitor, in humans. Drug Metab. Dispos. 42, 759-773.   DOI
13 Duggleby, R. G. (1995) Analysis of enzyme progress curves by nonlinear regression. Methods Enzymol. 249, 61-90.   DOI
14 Fukuda, T., Naganuma, M. and Kanai, T. (2019) Current new challenges in the management of ulcerative colitis. Intest. Res. 17, 36-44.   DOI
15 Gupta, P., Alvey, C. and Wang, R. (2012) Lack of effect of tofacitinib (CP-690,550) on the pharmacokinetics of the CYP3A4 substrate midazolam in healthy volunteers: confirmation of in vitro data. Br. J. Clin. Pharmacol. 74, 109-115.   DOI
16 Hussa, D. A. (2014) 2013 new drug update: what do new approvals hold for the elderly? Consult. Pharm. 29, 224-238.   DOI
17 Watkins, J. B., III and Sandeors, R. A. (1995) Diabetes mellitus-induced alterations of hepatobiliary function. Pharmacol. Rev. 47, 1-23.
18 Svein, O. and Theodor, W. G. (1982) Comparison of equilibrium time in dialysis experiments using spiked plasma or spiked buffer. J. Pharm. Sci. 71, 127-128.   DOI
19 Tahir, H. (2018) Therapies in ankylosing spondylitis-from clinical trials to clinical practice. Rheumatology (Oxford) 57, vi23-vi28.
20 Vincenti, F., Tedesco Silva, H., Busque, S., O'Connell, P., Friedewald, J., Cibrik, D., Budde, K., Yoshida, A., Cohney, S., Weimar, W., Kim, Y. S., Lawendy, N., Lan, S. P., Kudlacz, E., Krishnaswami, S. and Chan, G. (2012) Randomized phase 2b trial of tofacitinib (CP-690,550) in de novo kidney transplant patients: efficacy, renal function and safety at 1 year. Am. J. Transplant. 12, 2446-2456.   DOI
21 Kim, Y. C., Lee, A. K., Lee, J. H., Lee, I., Lee, D. C., Kim, S. H., Kim, S. G. and Lee, M. G. (2005) Pharmacokinetics of theophylline in diabetes mellitus rat: induction of CYP1A2 and CYP2E1 on 1,3-dimethyluric acid formation. Eur. J. Pharm. Sci. 26, 114-123.   DOI
22 Watkins, J. B. III and Sherman, S. E. (1992) Long-term diabetes alters the hepatobiliary clearance of acetaminophen, bilirubin and digoxin. J. Pharmacol. Exp. Ther. 260, 1337-1343.
23 Gibaldi, M. and Perrier, D. (1982) Pharmacokinetics, 2nd ed. Marcel-Dekker, New York.
24 Kennedy Crispin, M., Ko, J. M., Craiglow, B. G., Li, S., Shankar, G., Urban, J. R., Chen, J. C., Cerise, J. E., Jabbari, A., Winge, M. C., Marinkovich, M. P., Christiano, A. M., Oro, A. E. and King, B. A. (2016) Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata. JCI Insight 1, e89776.
25 Kim, S. H., Choi, Y. M. and Lee, M. G. (1993) Pharmacokinetics and pharmacodynamics of furosemide in protein-calorie malnutrition. J. Pharmacokinet. Biopharm. 21, 1-17.   DOI
26 Kim, S. H., Lee. J. S. and Lee, M. G. (1999) Stability, blood partition and plasma protein binding of ipriflavone, an isoflavone derivative. Biopharm. Drug Dispos. 20, 355-360.   DOI
27 LaBranchem, T, P., Jesson, M. I., Radi, Z. A., Storer, C. E., Guzova, J. A., Bonar, S. L., Thompson, J. M., Happa, F. A., Stewart, Z. S., Zhan, Y., Bollinger, C. S., Bansal, P. N., Wellen, J. W., Wilkie, D. P., Bailey, S. A., Symanowicz, P. T., Hegen, M., Head, R. D., Kishore, N., Mbalaviele, G. and Meyer, D. M. (2012) JAK inhibition with tofacitinib suppresses arthritic joint structural damage through decreased RANKL production. Arthritis Rheum. 64, 3531-3542.   DOI
28 Lawendy, N., Krishnaswami, S., Wang, R., Gruben, D., Cannon, C., Swan, S. and Chan, G. (2009) Effect of CP-690,550, an orally active janus kinase inhibitor, on renal function in healthy adult volunteers. J. Clin. Pharmacol. 49, 423-429.   DOI
29 Lee, J. S. and Kim, S. H. (2019) Dose-dependent pharmacokinetics of tofacitinib in rats: influence of hepatic and intestinal first-pass metabolism. Pharmaceutics 11, e318.
30 Lee, D. Y., Chung, H. J., Choi, Y. H., Lee, U., Kim, S. H., Lee, I. and Lee, M. G. (2009) Pharmacokinetics of ipriflavone and its two metabolites, M1 and M5, after the intravenous and oral administration of ipriflavone to rat model of diabetes mellitus induced by streptozotocin. Eur. J. Pharm. Sci. 38, 465-471.   DOI
31 Lee, D. Y., Lee, M. G., Shin, H. S. and Lee, I. (2007) Changes in omeprazole pharmacokinetics in rats with diabetes induced by alloxan or streptozotocin: faster clearance of omeprazole due to induction of hepatic CYP1A2 and 3A1. J. Pharm. Pharm. Sci. 10, 420-433.   DOI
32 Lee, J. H., Yang, S. H., Oh, J. M. and Lee, M. G. (2010) Pharmacokinetics of drugs in rats with diabetes mellitus induced by alloxan or streptozocin: comparison with those in patients with type I diabetes mellitus. J. Pharm. Pharmacol. 62, 1-23.   DOI
33 Levy, L. L., Urban, J. and King, B. A. (2015) Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate. J. Am. Acad. Dermatol. 73, 395-399.   DOI
34 Ma, G., Xie, R., Strober, B., Langley, R., Ito, K., Krishnaswami, S., Wolk, R., Valdez, H., Rottinghaus, S., Tallman, A. and Gupta, R. (2018) Pharmacokinetic characteristics of tofacitinib in adult patients with moderate to severe chronic plaque psoriasis. Clin. Pharmacol. Drug Dev. 7, 584-596.
35 Mitruka, B. M. and Rawnsley, H. M. (1981) Clinical Biomedical and Hematological Reference Values in Normal Experimental Animals and Normal Humans, 2nd ed. Masson Publishing, USA Inc., New York.
36 Chiou, W. L. (1978) Critical evaluation of the potential error in pharmacokinetic studies of using the linear trapezoidal rule method for the calculation of the area under the plasma level-time curve. J. Pharmacokinet. Biopharm. 6, 539-546.   DOI
37 Antonelli, E., Villanacci, V. and Bassotti, G. (2018) Novel oral-targeted therapies for mucosal healing in ulcerative colitis. World J. Gastroenterol. 24, 5322-5330.   DOI
38 Bachelez, H., van de Kerkhof, P. C., Strohal, R., Kubanov, A., Valenzuela, F., Lee, J. H., Yakusevich, V., Chimenti, S., Papacharalambous, J., Proulx, J., Gupta, P., Tan, H., Tawadrous, M., Valdez, H. and Wolk, R.; OPT Compare Investigators (2015) Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial. Lancet 386, 552-561.   DOI
39 Bae, S. H., Park, J. H., Choi, H. G., Kim, H. and Kim, S. H. (2018) Imidazole antifungal drugs inhibit the cell proliferation and invasion of human breast cancer cells. Biomol. Ther. (Seoul) 26, 494-502.   DOI
40 Carnovale, C. E., Marinelli, R. A. and Rodriguez Garay, E. A. (1986) Bile flow decrease and altered bile composition in streptozotocintreated rats. Biochem. Pharmacol. 35, 2625-2628.   DOI