PMID- 30488476
OWN - NLM
STAT- MEDLINE
DCOM- 20190418
LR  - 20200311
IS  - 1099-081X (Electronic)
IS  - 0142-2782 (Linking)
VI  - 40
IP  - 1
DP  - 2019 Jan
TI  - Effect of high uric acid on the disposition of metformin: in vivo and in vitro 
      studies.
PG  - 3-11
LID - 10.1002/bdd.2164 [doi]
AB  - Metformin is always used as the baseline antidiabetic therapy for patients with 
      type 2 diabetes mellitus (T2DM) and hyperuricemia. Metformin is excreted into 
      urine through active secretion mediated by rOCTs and rMATE1.The aim of this study 
      was to identify the effects of high uric acid on the disposition and its 
      mechanism. For the in vivo study, a hyperuricemic animal model was induced by 
      intraperitoneal injection of potassium oxonate (250 mg/kg) in rats. Metformin 
      (100 mg/kg) was administered orally to investigate the pharmacokinetics in 
      control and hyperuricemic rats, respectively. For the in vitro study, HEK293 and 
      HepaRG cells were used to investigate the effect of uric acid (15 mg/dl) on the 
      expression of OCT1, OCT2 and MATE1 and the disposition of metformin, 
      respectively. The in vivo study showed that the AUC(0 --> 600) of metformin was 
      significantly decreased by 33.3%, whereas the cumulative urinary excretion of 
      metformin was increased by 25.4% in hyperuricemic rats compared with that in 
      control rats. The renal rOCT1, rOCT2 and rMATE1 and hepatic rMATE1 levels were 
      increased in hyperuricemic rats compared with those in control rats, 
      respectively. The in vitro study showed that uric acid could upregulate the 
      expression of OCT2 and MATE1 in HEK293 cells and MATE1 in HepaRG cells and 
      increase the intracellular metformin concentration in these two cell lines. These 
      results demonstrated that a high uric acid level promoted urinary metformin 
      excretion and decreased the plasma metformin concentration; the in vivo and in 
      vitro studies provided a possible explanation being that high uric acid could 
      upregulate the expression of renal metformin transporters OCTs and MATE1.
CI  - (c) 2018 John Wiley & Sons, Ltd.
FAU - Zhang, Guoqiang
AU  - Zhang G
AD  - Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou, 
      730000, China.
FAU - Ma, Yanrong
AU  - Ma Y
AD  - Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou, 
      730000, China.
FAU - Xi, Dali
AU  - Xi D
AD  - Department of Pathology, the First Hospital of Lanzhou University, Lanzhou, 
      730000, China.
FAU - Rao, Zhi
AU  - Rao Z
AD  - Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou, 
      730000, China.
FAU - Sun, Xiaohan
AU  - Sun X
AD  - Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou, 
      730000, China.
AD  - College of Pharmaceutical Science, Lanzhou University, Lanzhou, 730000, China.
FAU - Wu, Xin'an
AU  - Wu X
AUID- ORCID: 0000-0002-3211-9730
AD  - Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou, 
      730000, China.
LA  - eng
GR  - 81373494/National Natural Science Foundation of China/
GR  - 81641142/National Natural Science Foundation of China/
GR  - 81702853/National Natural Science Foundation of China/
GR  - lzujbky-2017-84/Fundamental Research Funds for the Central Universities/
GR  - lzujbky-2018-55/Fundamental Research Funds for the Central Universities/
PT  - Journal Article
DEP - 20181218
PL  - England
TA  - Biopharm Drug Dispos
JT  - Biopharmaceutics & drug disposition
JID - 7911226
RN  - 0 (Antiporters)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Organic Cation Transport Proteins)
RN  - 0 (Organic Cation Transporter 1)
RN  - 0 (Organic Cation Transporter 2)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Slc47a1 protein, rat)
RN  - 268B43MJ25 (Uric Acid)
RN  - 4R7FFA00RX (potassium oxonate)
RN  - 5VT6420TIG (Oxonic Acid)
RN  - 9100L32L2N (Metformin)
SB  - IM
MH  - Animals
MH  - Antiporters/metabolism
MH  - Cell Line
MH  - Humans
MH  - Hyperuricemia/chemically induced/*metabolism/pathology
MH  - Hypoglycemic Agents/blood/*pharmacokinetics/urine
MH  - Kidney/metabolism/pathology
MH  - Liver/metabolism
MH  - Male
MH  - Metformin/blood/*pharmacokinetics/urine
MH  - Organic Cation Transport Proteins/metabolism
MH  - Organic Cation Transporter 1/metabolism
MH  - Organic Cation Transporter 2/metabolism
MH  - Oxonic Acid
MH  - Rats, Wistar
MH  - Recombinant Proteins/metabolism
MH  - Tissue Distribution
MH  - Uric Acid/blood
OTO - NOTNLM
OT  - MATE1
OT  - OCT1
OT  - OCT2
OT  - hyperuricemia
OT  - metformin
EDAT- 2018/11/30 06:00
MHDA- 2019/04/19 06:00
CRDT- 2018/11/30 06:00
PHST- 2018/07/10 00:00 [received]
PHST- 2018/10/29 00:00 [revised]
PHST- 2018/11/11 00:00 [accepted]
PHST- 2018/11/30 06:00 [pubmed]
PHST- 2019/04/19 06:00 [medline]
PHST- 2018/11/30 06:00 [entrez]
AID - 10.1002/bdd.2164 [doi]
PST - ppublish
SO  - Biopharm Drug Dispos. 2019 Jan;40(1):3-11. doi: 10.1002/bdd.2164. Epub 2018 Dec 
      18.