TY - JOUR
T1 - Determination of metformin bio-distribution by LC-MS/MS in mice treated with a clinically relevant paradigm
AU - Chaudhari, Kiran
AU - Wang, Jianmei
AU - Xu, Yong
AU - Winters, Ali
AU - Wang, Linshu
AU - Dong, Xiaowei
AU - Cheng, Eric Y.
AU - Liu, Ran
AU - Yang, Shao Hua
N1 - Funding Information:
This work was partly supported by the National Institutes of Health grants R01NS088596 (SY), R01NS109583 (SY), and American Heart Association Grant 17POST33670981 (KC)
Publisher Copyright:
Copyright: © 2020 Chaudhari et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2020/6
Y1 - 2020/6
N2 - Metformin, an anti-diabetes drug, has been recently emerging as a potential “anti-aging” intervention based on its reported beneficial actions against aging in preclinical studies. Nonetheless, very few metformin studies using mice have determined metformin concentrations and many effects of metformin have been observed in preclinical studies using doses/ concentrations that were not relevant to therapeutic levels in human. We developed a liquid chromatography-tandem mass spectrometry protocol for metformin measurement in plasma, liver, brain, kidney, and muscle of mice. Young adult male and female C57BL/6 mice were voluntarily treated with metformin of 4 mg/ml in drinking water which translated to the maximum dose of 2.5 g/day in humans. A clinically relevant steady-state plasma metformin concentrations were achieved at 7 and 30 days after treatment in male and female mice. Metformin concentrations were slightly higher in muscle than in plasma, while, ~3 and 6-fold higher in the liver and kidney than in plasma, respectively. Low metformin concentration was found in the brain at ~20% of the plasma level. Furthermore, gender difference in steady-state metformin bio-distribution was observed. Our study established steady-state metformin levels in plasma, liver, muscle, kidney, and brain of normoglycemic mice treated with a clinically relevant dose, providing insight into future metformin preclinical studies for potential clinical translation.
AB - Metformin, an anti-diabetes drug, has been recently emerging as a potential “anti-aging” intervention based on its reported beneficial actions against aging in preclinical studies. Nonetheless, very few metformin studies using mice have determined metformin concentrations and many effects of metformin have been observed in preclinical studies using doses/ concentrations that were not relevant to therapeutic levels in human. We developed a liquid chromatography-tandem mass spectrometry protocol for metformin measurement in plasma, liver, brain, kidney, and muscle of mice. Young adult male and female C57BL/6 mice were voluntarily treated with metformin of 4 mg/ml in drinking water which translated to the maximum dose of 2.5 g/day in humans. A clinically relevant steady-state plasma metformin concentrations were achieved at 7 and 30 days after treatment in male and female mice. Metformin concentrations were slightly higher in muscle than in plasma, while, ~3 and 6-fold higher in the liver and kidney than in plasma, respectively. Low metformin concentration was found in the brain at ~20% of the plasma level. Furthermore, gender difference in steady-state metformin bio-distribution was observed. Our study established steady-state metformin levels in plasma, liver, muscle, kidney, and brain of normoglycemic mice treated with a clinically relevant dose, providing insight into future metformin preclinical studies for potential clinical translation.
UR - http://www.scopus.com/inward/record.url?scp=85086354224&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0234571
DO - 10.1371/journal.pone.0234571
M3 - Article
C2 - 32525922
AN - SCOPUS:85086354224
SN - 1932-6203
VL - 15
JO - PLoS ONE
JF - PLoS ONE
IS - 6
M1 - e0234571
ER -