Combined treatment of tacrolimus and everolimus increases oxidative stress by pharmacological interactions.
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.
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.
Shang Guo
SG
Piao
Sun Woo
SW
Lim
Kyoung Chan
KC
Doh
Long
L
Jin
Seong Beom
SB
Heo
Yu Fen
YF
Zheng
Su Kyung
SK
Bae
Byung Ha
BH
Chung
Can
C
Li
Chul Woo
CW
Yang
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D000068338:Everolimus; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*
D015415:Biomarkers; D007166:Immunosuppressive Agents; D000080242:8-Hydroxy-2'-Deoxyguanosine; D000068338:Everolimus; D003849:Deoxyguanosine; D020123:Sirolimus; D016559:Tacrolimus