PMID- 25912929
OWN - NLM
STAT- MEDLINE
DCOM- 20160318
LR  - 20211203
IS  - 1744-764X (Electronic)
IS  - 1474-0338 (Print)
IS  - 1474-0338 (Linking)
VI  - 14
IP  - 7
DP  - 2015 Jul
TI  - Everolimus and sirolimus in transplantation-related but different.
PG  - 1055-70
LID - 10.1517/14740338.2015.1040388 [doi]
AB  - INTRODUCTION: The inhibitors of the mammalian target of rapamycin (mTOR) 
      sirolimus and everolimus are used not only as immunosuppressants after organ 
      transplantation in combination with calcineurin inhibitors (CNIs) but also as 
      proliferation signal inhibitors coated on drug-eluting stents and in cancer 
      therapy. Notwithstanding their related chemical structures, both have distinct 
      pharmacokinetic, pharmacodynamic and toxicodynamic properties. AREAS COVERED: The 
      additional hydroxyethyl group at the C(40) of the everolimus molecule results in 
      different tissue and subcellular distribution, different affinities to active 
      drug transporters and drug-metabolizing enzymes as well as differences in 
      drug-target protein interactions including a much higher potency in terms of 
      interacting with the mTOR complex 2 than sirolimus. Said mechanistic differences 
      as well as differences found in clinical trials in transplant patients are 
      reviewed. EXPERT OPINION: In comparison to sirolimus, everolimus has higher 
      bioavailability, a shorter terminal half-life, different blood metabolite 
      patterns, the potential to antagonize the negative effects of CNIs on neuronal 
      and kidney cell metabolism (which sirolimus enhances), the ability to stimulate 
      mitochondrial oxidation (which sirolimus inhibits) and to reduce vascular 
      inflammation to a greater extent. A head-to-head, randomized trial comparing the 
      safety and tolerability of these two mTOR inhibitors in solid organ transplant 
      recipients is merited.
FAU - Klawitter, Jost
AU  - Klawitter J
AD  - University of Colorado, iC42 Clinical Research and Development , Anschutz Medical 
      Campus, 1999 North Fitzsimons Parkway, Suite 100, Aurora, CO 80045-7503 , USA +1 
      303 724 5665 ; +1 303 724 5662 ; uwe.christians@ucdenver.edu.
FAU - Nashan, Bjorn
AU  - Nashan B
FAU - Christians, Uwe
AU  - Christians U
LA  - eng
GR  - R01 HD070511/HD/NICHD NIH HHS/United States
GR  - R01HD70511/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20150426
PL  - England
TA  - Expert Opin Drug Saf
JT  - Expert opinion on drug safety
JID - 101163027
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Multiprotein Complexes)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Biological Availability
MH  - *Everolimus/metabolism/pharmacokinetics
MH  - Graft Rejection/metabolism/prevention & control
MH  - Humans
MH  - Immunosuppressive Agents/metabolism/pharmacokinetics
MH  - Kidney/*metabolism
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Mitochondria/*drug effects
MH  - *Multiprotein Complexes/antagonists & inhibitors/metabolism
MH  - Neurons/*metabolism
MH  - *Sirolimus/metabolism/pharmacokinetics
MH  - *TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
PMC - PMC6053318
MID - NIHMS978086
OTO - NOTNLM
OT  - comparison
OT  - drug metabolism
OT  - everolimus
OT  - mammalian target of rapamycin complex 2
OT  - mitochondria
OT  - nephrotoxicity
OT  - neuronal metabolism
OT  - pharmacokinetics
OT  - sirolimus
OT  - vascular inflammation
COIS- Declaration of Interests BN has received research funding and honoraria from 
      Novartis Pharma and has served on Novartis Pharma advisory committees. JK and UC 
      have received research funding from Novartis Pharma. The authors have no other 
      relevant affiliations or financial involvement with any organization or entity 
      with a financial interest in or financial conflict with the subject matter or 
      materials discussed in the manuscript. This includes employment, consultancies, 
      honoraria, stock ownership or options, expert testimony, grants or patents, 
      received or pending, or royalties.
EDAT- 2015/04/29 06:00
MHDA- 2016/03/19 06:00
PMCR- 2018/07/19
CRDT- 2015/04/28 06:00
PHST- 2015/04/28 06:00 [entrez]
PHST- 2015/04/29 06:00 [pubmed]
PHST- 2016/03/19 06:00 [medline]
PHST- 2018/07/19 00:00 [pmc-release]
AID - 10.1517/14740338.2015.1040388 [doi]
PST - ppublish
SO  - Expert Opin Drug Saf. 2015 Jul;14(7):1055-70. doi: 10.1517/14740338.2015.1040388. 
      Epub 2015 Apr 26.