Shang Guo Piao1, Sun Woo Lim, Kyoung Chan Doh, Long Jin, Seong Beom Heo, Yu Fen Zheng, Su Kyung Bae, Byung Ha Chung, Can Li, Chul Woo Yang. 1. 1 CRCiD, Seoul St. Mary's Hospital, Seoul, South Korea. 2 Transplant research center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. 3 Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. 4 College of Pharmacy, Seoul National University, Seoul, South Korea. 5 College of Pharmacy, The Catholic University of Korea, Bucheon, South Korea. 6 Nephrology & Dialysis Unit, Department of Internal Medicine, YanBian University Hospital, JiLin, China. 7 Address correspondence to: Chul Woo Yang, M.D., Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-Gu, 137-701, Seoul, South Korea.
Abstract
BACKGROUND: Drug-drug interaction between everolimus (EVR) and tacrolimus (TAC) is still undetermined. We evaluated whether EVR enhances TAC-induced organ injury through drug-drug interaction. METHODS: Tacrolimus (6 mg/kg) was given to rats with or without EVR (1 or 2 mg/kg) orally for 4 weeks. The influences of EVR on TAC-induced organ injury were evaluated in terms of nephrotoxicity and pancreatic islet dysfunction. Drug-drug interaction was evaluated by measuring the level of each drug in the blood and target tissue, and the correlation between the two drugs was observed in the blood and target tissue. The concentration of 8-hydroxy-2'-deoxyguanosine in blood or urine was measured as a marker of oxidative stress, and correlation between drug levels and oxidative stress was also evaluated. RESULTS: Tacrolimus treatment alone did not cause overt renal or pancreatic islet injury, but the addition of EVR significantly enhanced the TAC-induced organ injury, as demonstrated by aggravated nephrotoxicity and pancreatic islet dysfunction. The combination of EVR and TAC significantly increased each drug level in the target tissues as well as in blood, and there was good correlation between the two drugs in blood and target organs. The serum and urinary levels of 8-hydroxy-2'-deoxyguanosine were significantly increased in the TAC+EVR group compared with the TAC- or EVR-alone group and were well correlated with drug levels in blood and tissues. CONCLUSIONS: Everolimus enhances TAC-induced target organ injury by increasing oxidative stress via pharmacological interaction in blood and target tissue. This finding provides a better understanding of the effects of EVR when used in combination with TAC.
BACKGROUND: Drug-drug interaction between everolimus (EVR) and tacrolimus (TAC) is still undetermined. We evaluated whether EVR enhances TAC-induced organ injury through drug-drug interaction. METHODS:Tacrolimus (6 mg/kg) was given to rats with or without EVR (1 or 2 mg/kg) orally for 4 weeks. The influences of EVR on TAC-induced organ injury were evaluated in terms of nephrotoxicity and pancreatic islet dysfunction. Drug-drug interaction was evaluated by measuring the level of each drug in the blood and target tissue, and the correlation between the two drugs was observed in the blood and target tissue. The concentration of 8-hydroxy-2'-deoxyguanosine in blood or urine was measured as a marker of oxidative stress, and correlation between drug levels and oxidative stress was also evaluated. RESULTS:Tacrolimus treatment alone did not cause overt renal or pancreatic islet injury, but the addition of EVR significantly enhanced the TAC-induced organ injury, as demonstrated by aggravated nephrotoxicity and pancreatic islet dysfunction. The combination of EVR and TAC significantly increased each drug level in the target tissues as well as in blood, and there was good correlation between the two drugs in blood and target organs. The serum and urinary levels of 8-hydroxy-2'-deoxyguanosine were significantly increased in the TAC+EVR group compared with the TAC- or EVR-alone group and were well correlated with drug levels in blood and tissues. CONCLUSIONS:Everolimus enhances TAC-induced target organ injury by increasing oxidative stress via pharmacological interaction in blood and target tissue. This finding provides a better understanding of the effects of EVR when used in combination with TAC.
Authors: Ji Hyun Yu; Sun Woo Lim; Kang Luo; Sheng Cui; Yi Quan; Yoo Jin Shin; Kyung Eun Lee; Hong Lim Kim; Eun Jeong Ko; Byung Ha Chung; Ju Hwan Kim; Sang J Chung; Chul Woo Yang Journal: FASEB J Date: 2019-08-20 Impact factor: 5.191
Authors: Kang Luo; Sun Woo Lim; Jian Jin; Long Jin; Hyo Wook Gil; Dai Sig Im; Hyeon Seok Hwang; Chul Woo Yang Journal: BMC Nephrol Date: 2019-06-14 Impact factor: 2.388
Authors: Kang Luo; Ji Hyun Yu; Yi Quan; Yoo Jin Shin; Kyung Eun Lee; Hong Lim Kim; Eun Jeong Ko; Byung Ha Chung; Sun Woo Lim; Chul Woo Yang Journal: Sci Rep Date: 2019-05-29 Impact factor: 4.379