PMID- 32215854
OWN - NLM
STAT- MEDLINE
DCOM- 20210412
LR  - 20210622
IS  - 2299-5684 (Electronic)
IS  - 1734-1140 (Linking)
VI  - 72
IP  - 3
DP  - 2020 Jun
TI  - Changes in PCSK9 and LDL cholesterol concentrations by everolimus treatment and 
      their effects on polymorphisms in PCSK9 and mTORC1.
PG  - 622-630
LID - 10.1007/s43440-020-00090-6 [doi]
AB  - BACKGROUND: The purpose of this study was to evaluate the effects of 
      concentrations of proprotein convertase subtilisin/kexin type 9 (PCSK9) and 
      low-density lipoprotein (LDL) cholesterol by the mammalian target of rapamycin 
      (mTOR) inhibitor everolimus and their effects on genetic polymorphisms in the 
      PCSK9 and mTORC1 genes in 53 renal transplant recipients. METHODS: Prior to and 
      on day 15 after everolimus administration, the concentrations of everolimus in 
      blood and PCSK9 and LDL cholesterol in plasma were evaluated. Additionally, 
      mTORC1 (rs2536T>C and rs2295080T>G) and PCSK9 (rs505151G>A, rs562556G>A, and 
      rs11593680C>T) polymorphisms were analyzed. RESULTS: Mean PCSK9 plasma 
      concentrations on day 15 after everolimus treatment were significantly higher 
      than those before treatment (295 versus 214 ng/mL, respectively; p = 0.004). 
      Significant correlations between the area under the blood concentration-time 
      curves (AUC)(0-12) on day 15 of everolimus treatment and the change rate in PCSK9 
      concentrations were found (r = 0.316, p = 0.021). However, there were no 
      significant correlations between the change rate in PCSK9 and LDL cholesterol 
      concentrations. The change rate in PCSK9 concentrations by everolimus treatment 
      was significantly greater in patients with the mTORC1 rs2295080G allele than the 
      T/T genotype (p = 0.006); however, there were no significant differences between 
      PCSK9 rs505151G>A and rs11583680C>T genotypes. In multivariate analyses, patients 
      with mTORC1 rs2295080G (p = 0.010), higher everolimus AUC(0-12) (p = 0.006), and 
      female sex (p = 0.029) showed higher change rates of PCSK9 following everolimus 
      therapy. CONCLUSIONS: Administration of everolimus significantly elevated plasma 
      PCSK9 concentrations, potentially causing everolimus-induced hyperlipidemia.
FAU - Sato, Shiori
AU  - Sato S
AD  - Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, 
      Japan.
FAU - Akamine, Yumiko
AU  - Akamine Y
AD  - Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, 
      Japan.
FAU - Kagaya, Hideaki
AU  - Kagaya H
AD  - Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, 
      Japan.
FAU - Saito, Mitsuru
AU  - Saito M
AD  - Department of Urology, Akita University School of Medicine, 1-1-1 Hondo, Akita, 
      Japan.
FAU - Inoue, Takamitsu
AU  - Inoue T
AD  - Department of Urology, Akita University School of Medicine, 1-1-1 Hondo, Akita, 
      Japan.
FAU - Numakura, Kazuyuki
AU  - Numakura K
AD  - Department of Urology, Akita University School of Medicine, 1-1-1 Hondo, Akita, 
      Japan.
FAU - Habuchi, Tomonori
AU  - Habuchi T
AD  - Department of Urology, Akita University School of Medicine, 1-1-1 Hondo, Akita, 
      Japan.
FAU - Satoh, Shigeru
AU  - Satoh S
AD  - Center for Kidney Disease and Transplantation, Akita University Hospital, 1-1-1 
      Hondo, Akita, Japan.
FAU - Miura, Masatomo
AU  - Miura M
AD  - Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, 
      Japan. m-miura@hos.akita-u.ac.jp.
LA  - eng
PT  - Journal Article
DEP - 20200325
PL  - Switzerland
TA  - Pharmacol Rep
JT  - Pharmacological reports : PR
JID - 101234999
RN  - 0 (Cholesterol, LDL)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 3.4.21.- (PCSK9 protein, human)
RN  - EC 3.4.21.- (Proprotein Convertase 9)
SB  - IM
MH  - Cholesterol, LDL/*blood/*genetics
MH  - Everolimus/*pharmacology
MH  - Female
MH  - Humans
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors
MH  - Polymorphism, Genetic/*drug effects
MH  - Proprotein Convertase 9/*blood/*genetics
OTO - NOTNLM
OT  - Everolimus
OT  - Low-density lipoprotein cholesterol
OT  - Mammalian target of rapamycin complex 1
OT  - Polymorphism
OT  - Proprotein convertase subtilisin/kexin type 9
EDAT- 2020/03/28 06:00
MHDA- 2021/04/13 06:00
CRDT- 2020/03/28 06:00
PHST- 2019/09/09 00:00 [received]
PHST- 2020/02/20 00:00 [accepted]
PHST- 2020/02/17 00:00 [revised]
PHST- 2020/03/28 06:00 [pubmed]
PHST- 2021/04/13 06:00 [medline]
PHST- 2020/03/28 06:00 [entrez]
AID - 10.1007/s43440-020-00090-6 [pii]
AID - 10.1007/s43440-020-00090-6 [doi]
PST - ppublish
SO  - Pharmacol Rep. 2020 Jun;72(3):622-630. doi: 10.1007/s43440-020-00090-6. Epub 2020 
      Mar 25.