Journal of Pharmacological Sciences xxx (xxxx) xxx

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Journal of Pharmacological Sciences

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Full Paper

The influence of telmisartan on metformin pharmacokinetics and

pharmacodynamics
Jiagen Wen a, b, Meizi Zeng a, c, Zhaoqian Liu a, d, Honghao Zhou a, d, Heng Xu e,
Min Huang f, Wei Zhang a, d, *
a
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China
b
School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
c
Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
d
Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China
e
Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key
Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
f
School of Pharmaceutical Science, Sun Yat-Sen University, GuangZhou, GuangDong, China

a r t i c l e i n f o a b s t r a c t

Article history: Metformin is the most widely used drug among type 2 diabetes mellitus patients. However, drug
Received 14 January 2018 interaction on metformin will influence its glucose-lowering effect or increase its side effect of lactic
Received in revised form acidosis. In this study, a randomized, two-stage, crossover study was conducted to unveil the potential
1 November 2018
drug interaction between metformin and the anti-hypertension drug, telmisartan. Totally, 16 healthy
Accepted 19 November 2018
Available online xxx
Chinese male volunteers were enrolled. Blood samples from various time-points after drug adminstra-
tion were analyzed for metformin quantification. Oral glucose tolerance test (OGTT) was conducted 2 h
after metformin administration. The AUC0-12 and Cmax of metformin in subjects co-administrated with
Keywords:
Telmisartan
telmisartan were significantly lower than with placebo. The geometric mean ratios (value of metformin
Metformin plus telmisartan phase/value of metformin plus placebo phase) for Cmax and AUC0-12 is 0.7972 (90%CI:
Pharmacokinetics 0.7202e0.8824) and 0.8336 (90%CI: 0.7696e0.9028), respectively. Moreover, telmisartan co-
Pharmacodynamics administration significantly increased the plasma concentrations of both glucose and insulin at 0.5 h
Drugedrug interaction since OGTT (7.64 ± 1.86 mmol/l$min vs 6.77 ± 0.83 mmol/l$min, P ¼ 0.040; 72.91 ± 31.98 mIU/ml$min vs
60.20 ± 24.20 mIU/ml$min, P ¼ 0.037), though the AUC of glucose and insulin after OGTT showed no
significant difference. These findings suggested that telmisartan had a significant influence on the
Pharmacokinetics of metformin in healthy groups, though the influence on glucose-lowering effect was
moderate.
© 2018 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological
Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).

1. Introduction is often co-administrated with other types of anti-diabetic drugs.2

Metformin (1,1-dimethylbiguanide) is the most frequently pre-
scribed drug for the treatment of type 2 diabetes mellitus. It de-
creases the blood glucose concentration mainly through inhibiting
gastrointestinal glucose absorption and hepatic glucose production
and increasing the glucose uptake and insulin sensitivity in mus-
cle.1 During the medication of type 2 diabetes mellitus, metformin
* Corresponding author. Department of Clinical Pharmacology, Xiangya Hospital,
Central South University, ChangSha, 410078, China. Fax: þ86 0731 8235 4476.
E-mail address: yjsd2003@163.com (W. Zhang).
Peer review under responsibility of Japanese Pharmacological Society.
Moreover, a proportion of diabetic patients are vulnerable to
other diseases such as infection, hypertension, hyperlipemia, car-
diovascular events and nephropathy, which means kinds of drugs
will be given to diabetic patients as well as anti-diabetic drugs.3e5
Therefore, drug-drug interaction during anti-diabetic therapy
should be cautious.
Hypertension is the most common complication of diabetes
mellitus, affecting more than 10% of diabetic patients.6 Antihyper-
tensive agents telmisartan, one of Angiotensin II 1 (AT1) receptor
antagonists, is often prescribed to diabetic patients, not only
because it decrease blood pressure efficiently but also it is of great
merits in alleviating diabetic nephrotoxicity.7 As an oral

https://doi.org/10.1016/j.jphs.2018.11.007
1347-8613/© 2018 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article as: Wen J et al., The influence of telmisartan on metformin pharmacokinetics and pharmacodynamics, Journal of
Pharmacological Sciences, https://doi.org/10.1016/j.jphs.2018.11.007
2 J. Wen et al. / Journal of Pharmacological Sciences xxx (xxxx) xxx
administration drug, telmisartan accumulates largely in liver and
has an inhibitory effect on CYP450 enzymes such as CYP2C8,8
CYP2C99 and CYP2J2.10 Furthermore, several studies demon-
strated that telmisartan can inhibit the ABCG2-, ABCB1-, OAT1-and
OCT2-mediated drug transporting.11,12 According to the studies of
human volunteers, telmisartan can interfere the metabolism of
arachidonic acid8,9 and increase the systemic concentration of
rosuvastatin.11 Although it is commonly used combined with
metformin, there is no reported study on the drug-drug interaction
between telmisartan and metformin.
Therefore, in present study, a randomized, double-blind, two-
way crossover and placebo controlled trial was employed to
investigate the effects of telmisartan on the pharmacokinetics and
pharmacodynamics of metformin.
2. Materials and methods
2.1. Subjects
Sixteen healthy male subjects (age 25 ± 4 years; height
173.3 ± 5.5 cm; weight 64.5 ± 5.4 kg; BMI 21.42 ± 0.78; fasting
plasma glucose 4.94 ± 0.31 mmol/l) were recruited in this study.
Exclusion criteria were anaemia (haemoglobin <12 g/dl), history of
drug abuse, symptomatic coronary heart disease, significant
elevation of hepatic enzyme levels (aspartate aminotransferase
[AST] or alanine aminotransferase [ALT] > 60 IU/l), serum
creatinine > 1.5 mg/dl, fasting plasma glucose > 6.1 mmol/L or
presenting any one of the criteria for metabolic syndrome. Subjects
who were consuming more than 2 alcoholic drinks (at one time)
twice a week, smoking more than 10 cigarettes a day, or taking any
medication were also excluded.
2.2. Study design
A randomized crossover study with two phases and a washout
period of 4 weeks was carried out. The study was approved by the
Ethics Committee of Institute of Clinical Pharmacology, Central
South University (Project No: CTXY-140007-1) and registered in
Chinese Clinical Trial Registry (ChiCTR-IPR-14005491).
All participants signed the informed consent before the clinical
trial. Once enrolled, participants were advised to maintain stable
activity levels (without periods of strenuous exercise) for 7 days
before the formal study. Approximately 3 days prior to the study,
subjects met with a dietitian to create a 3-day meal plan that
maintained carbohydrate intake at 200e250 g/day. The volunteers
recorded their food intake in a 3-day food diary. The last meal
before admission was eaten in the Clinical Trials Centre at Xiangya
Hospital. All subjects were divided into two groups (group one,
n ¼ 8; group two, n ¼ 8) randomly. The volunteers took 80 mg
telmisartan (Boehringer Ingelheim Pharma GmbH & Co. KG, Ger-
many) or placebo orally once daily at 08.00 h for 7 days. At 20.00 h
on day 6, the participants received a 500 mg oral dose of metformin
(Shenzhen Neptunus Pharmaceutical. Co., Ltd, China). After an
overnight fast at 08.00 h on day 7, subjects were given another dose
of 750 mg metformin (Shenzhen Neptunus Pharmaceutical. Co.,
Ltd, China) together with telmisartan or placebo. Two hours after
metformin administration an oral glucose tolerance test (OGTT)
was immediately conducted following ingestion of a 75-g glucose
load (Chongqing Heping Pharmaceutical Co., Ltd, China).
Carbohydrate-controlled meals were provided 5 h after the second
dose of metformin. After a washing period of 4 weeks, all subjects
entered into the study of next phase. In the stage two, one partic-
ipant experienced vomiting after ingestion of 75 g glucose. The
OGTT data of this participant was excluded, while his pharmaco-
kinetic data of metformin was kept.
Please cite this article as: Wen J et al., The influence of telmisartan on metformin pharmacokinetics and pharmacodynamics, Journal of
Pharmacological Sciences, https://doi.org/10.1016/j.jphs.2018.11.007
2.3. Sample collection
In each period, indwelling catheter was inserted in the forearm
at 0 h (predose) on Day 7. To determine metformin concentrations
in the plasma, blood samples were collected at 0.5, 1, 1.5, 2, 2.5, 3,
3.5, 4, 6, 8, 10 and 12 h after the second dose of metformin. For OGTT
analysis, blood samples were collected immediately before the
ingestion of glucose and at 15, 30, 45, 60, 90, 120 and 180 min after
ingestion. Blood samples were centrifuged and separated. All
samples were frozen at 80  C pending assaying.
2.4. Metformin and insulin concentration analysis
The detection of metformin was performed on a Shimadzu LC-
2010C HPLC system (Kyoto, Japan) with autosampler and ultravio-
let detector. The Class-VP software (Shimadzu) was used for data
analysis and processing. Compounds was separated on a Hypersil
BDS C18 column (4.6 mm*200 mm, 5 mm particle size) with a
Phenomenex Security GuardTM guard column (Phenomenex, US)
and quantified by UV detection at 232 nm. The mobile phase was
composed of 0.1 M phosphate buffer (with 0.3% triethylamine and
0.036% sodium dodecyl sulfate): acetonitrile ¼ 25:75 (V: V), and
was delivered at a flow rate of 1.0 ml/min. Metformin was used as
an external standard. Sample was prepared as the following pro-
cedure: 200 ml of plasma were mixed with 400 ml of acetonitrile in a
1.5 ml plastic tube and the mixture was vortexed for 5 min. After
centrifugation for 10 min at 13000 r/min, the supernatants were
transferred into an injection vial, and 20 ml was injected into the
HPLC. The good linear relationship of metformin was obtained in
the range of 25.0e5000 ng/ml, with the regression equation of
Y ¼ e 0.1022685 þ 1.08618325*X (r2 ¼ 0.99627). The limit of
metformin detection was 25.0 ng/mL. The intraday and interday
coefficients of variation were <10%. The sample recovery ranged
from 95% to 105% and the RSD was 1.92%.
2.5. Glucose and insulin concentration analysis
The pharmacodynamics of metformin was characterized by the
plasma insulin and blood glucose responses. Serum insulin and
blood glucose concentrations were measured by fully automatic
biochemical detector immediately after sampling. The plasma in-
sulin response was characterized by determining the fasting insulin
concentration (FINS), the threshold value for insulin resistance
(HOMA-IR) and the threshold value for insulin secretion (HOMA-
IS). The threshold value for insulin resistance (HOMA-IR) and the
threshold value for insulin secretion (HOMA-IS) were calculated
with the following equations:
HOMA-IR¼FINS  FPG/22.5
HOMA-IS ¼ 20  FINS/(FPG-3.5)
The blood glucose response was AUC0-3, maximum concentra-
tion. The AUC values were calculated by the linear trapezoidal rule.
2.6. Pharmacokinetics
The Pharmacokinetic parameters were calculated by non-
compartmental analysis using DAS 3.20. Maximum metformin
concentration (Cmax) and the time of maximum concentration
(Tmax) were determined, and the area under the metformin
concentrationetime curves for the time period 0e12 h (AUC0-12)
were calculated using the linear trapezoidal rule. The elimination
rate constant (ke) was estimated from the slope of the best-fit line
determined by linear regression analysis of the log-transformed
 J. Wen et al. / Journal of Pharmacological Sciences xxx (xxxx) xxx
concentrationetime curve. The elimination half-life (t1/2) was then
calculated from the equation t1/2 ¼ ln (2)/ke.
2.7. Statistical analysis
Measurements from the same subjects after telmisartan or
placebo treatment were compared using the paired samples t test.
Data were expressed as mean values ± standard deviation (SD). The
data were analyzed using SPSS v.19.0 (IMB Corp., Armonk, NY, USA).
P < 0.05 was considered significant. The associated drugedrug
interaction was assessed based on the 90% CIs of geometric mean
ratios (metformin þ telmisartan to metformin þ placebo) for the
primary pharmacokinetic parameters (Cmax and AUC0-12). It was
concluded that a significant pharmacokinetic interaction existed
between the two drugs if the 90% CI values did not fall within the
range of 0.80e1.25.13
3. Results
3.1. Effects of telmisartan on metformin pharmacokinetics
The plasma concentrationetime profiles of metformin com-
bined with telmisartan or placebo were shown in Fig. 1 and the
parameters of metformin were shown in Table 1. The AUC0-12 and
Cmax of metformin mono-administration were consistent with the
previous studies.14 As shown in Table 1, the Cmax values and AUC0-12
of metformin significantly decreased by 20.8% (1156.31 ± 373.62 vs
1459.32 ± 527.68, P ¼ 0.001) and 17.6% (5379.26 ± 1713.50 vs
6524.73 ± 2597.50, P ¼ 0.004), respectively, when co-administrated
with telmisartan. However, telmisartan co-administration did not
significantly change the parameter of Tmax and T1/2. The geometric
mean ratios of metformin plus telmisartan to metformin for Cmax
and AUC0-12 is 0.7972 (90% CI: 0.7202e0.8825) and 0.8336 (90% CI:
0.7696e0.9028), which fall out of the range of 0.8e1.25.
3.2. Effects of telmisartan on metformin pharmacodynamics
Healthy volunteers (n ¼ 15) underwent oral glucose tolerance
tests (OGTTs) after receiving two doses of metformin in combina-
tion with placebo or telmisartan. The FINS, HOMA-IR and HOMA-IS
between the two treatments were not significant different
(Table 2). The plasma glucose/insulin concentrationetime curves
Fig. 1. The plasma concentrationetime curve of metformin. Metformin concentrations
were measured after the second dose of metformin. Data are expressed as mean ± SD
(n ¼ 16). *P < 0.05 (Metformin plus telmisartan treatment vs.metformin plus placebo
treatment).
Please cite this article as: Wen J et al., The influence of telmisartan on metformin pharmacokinetics and pharmacodynamics, Journal of
Pharmacological Sciences, https://doi.org/10.1016/j.jphs.2018.11.007
3
after OGTTs are shown in Fig. 2A and B. Only at 0.5 h since OGTT,
telmisartan treatment significant increased plasma concentration
of glucose and insulin (7.64 ± 1.86 mmol/l$min vs
6.77 ± 0.83 mmol/l$min, P ¼ 0.040; 72.91 ± 31.98 mIU/ml$min and
60.20 ± 24.20 mIU/ml$min, P ¼ 0.037), but the AUC of glucose and
insulin for the entire 180-min test concentrationetime showed no
difference (18.81 ± 3.19 mmol/l$min and 17.64 ± 1.81 mmol/l$min,
P ¼ 0.089; 147.90 ± 73.87 mIU/ml$min and 131.81 ± 65.17 mIU/
ml$min P ¼ 0.167) (Table 2).
4. Discussion
Metformin is a cationic drug and exerts the glucose-lowering
effect after oral administration. The oral absorption and hepatic
uptake of metformin are mediated possibly by organic cation
transporters, whereas its excretion is mainly via renal drug trans-
porters OCT2 and MATEs.15 Drug interactions upon these trans-
porters can have a special influence on metformin
pharmacokinetics. For example, MATEs or OCT2 inhibitors,
ondansetron16 and rabeprazole,17 can increase the plasma con-
centration of metformin. Although telmisartan was founded with a
moderate effect of OCT2 inhibiting, the coadministration of telmi-
sartan can decrease the plasma concentration of metformin. In
particular, the geometric mean ratios of metformin plus telmisartan
to metformin for Cmax and AUC0-12 are 0.7972 (90% CI:
0.7202e0.8824) and 0.8336 (90% CI: 0.7696e0.9028). The ratios fall
out of the range of 0.8e1.25, which means a possible pharmaco-
kinetic interaction between the two drugs. Considering that the
effects of telmisartan is lowering metformin plasma concentration,
the role of telmisartan on metformin may not depend on renal
transporters OCT2 and MATEs.
As an oral administration drug, the absorption of telmisartan is
mainly through intestine, with a bioavailability of 40e60%.18 Un-
like most kinds of drug, less than 1% of telmisartan was eliminated
via kidney and most of the drug were excreted through feces in its
original form.18,19 Because telmisartan has low water-solubility,
there will be a maximum concentration in gastrointestinal tracts.
The observed decrease in plasma levels of metformin may result in
the direct inhibition of telmisartan on metformin absorption from
the gastrointestinal tract. Studies have indicated the inhibition of
OCT1 decreased metformin hepatic uptake,20 and the OCT2 inhi-
bition by rabeprazole reduced its kidney elimination resulting in
the increase of its systemic concentration.17 OCT3 and PMAT
localized on the luminal side of intestinal epithelial cells, respon-
sible for metformin absorption.21,22 Although no investigation of
telmisartan on OCT3 or PMAT were given, possible it is that tel-
misartan also have an inhibitory effect on OCT3-or PMAT-
mediated metformin absorption. Also, the protein binding ratio
of telmisartan is as high as 99.5%, which means the free form of
telmisartan in plasma is of quite low level. Thus, it is unlike tel-
misartan has the ability of inhibiting metformin hepatic uptake or
renal excretion.
Although the protein binding ratio of telmisartan is high, nearly
none of metformin binds to plasma albumin. Thus, it is impossible
that telmisartan alters the metformin concentration through
competitive or incompetitive binding to albumin. Moreover, the
majority of metformin after absorption is in its natural form, which
functions in glucose lowering effect. It was reported that telmi-
sartan had inhibitory effect on CYP2C8, CYP2C9 and CYP2J2810.
However, it will not affect the Pharmacokinetics of metformin
through inhibiting metabolic enzymes. At present, a number of
studies demonstrated that telmisartan can act as a partial agonist of
peroxisome proliferator-activated receptor-gamma (PPARg) and
activate Akt/GSK-3b and AMPK.23e25 As a drug of long-term use, it
is also hypothesized that telmisartan may induce the expression of
4 J. Wen et al. / Journal of Pharmacological Sciences xxx (xxxx) xxx

Table 1
Pharmacokinetic parameters of metformin in healthy participants (n ¼ 16) after telmisartan and placebo treatment.

PK parameter MþT M p Geometric Mean Ratio (M þ T)/T

Ratio 90% CI

Cmax (ng/mL) 1156.31 ± 373.62 1459.32 ± 527.68 0.001 0.8336 0.7696e0.9028

AUC0-12 (ng/mL$h) 5379.26 ± 1713.50 6524.73 ± 2597.50 0.004 0.7972 0.7202e0.8825
Tmax (h) 1.34 ± 0.85 1.41 ± 0.66 0.787 0.9050 0.6529e1.2546
T1/2 (h) 2.94 ± 1.72 2.41 ± 1.48 0.238 1.2055 0.9073e1.6015

Data were evaluated by the paired samples t test and are expressed as mean ± SD. AUC0-12, area under the plasma concentrationetime curve of metformin from time point 0 h
to time point 12 h; Cmax, maximum plasma concentration; T1/2, elimination half e time; Tmax, time of maximum plasma concentration; M, metformin; M þ T, metformin plus
telmisartan.

Table 2
The oral glucose tolerance test (OGTT) parameters of metformin after telmisartan
and placebo treatment in healthy participants (n ¼ 15).

Parameters MþT M p

AUCglu0-3 (mmol/L∙min) 18.81 ± 3.19 17.64 ± 1.81 0.089

AUCins0-3 (mIU/ml∙min) 147.90 ± 73.87 131.81 ± 65.17 0.167
Cglu0.5 (mmol/L) 7.64 ± 1.86 6.77 ± 0.83 0.040
Cins0.5 (mIU/ml) 72.91 ± 31.98 60.20 ± 24.20 0.037
FINS (mIU/ml) 6.39 ± 4.85 4.96 ± 5.11 0.130
HOMA-IR 1.44 ± 1.131 1.07 ± 1.09 0.071
HOMA-IS 85.15 ± 59.82 79.27 ± 81.56 0.720

Data were evaluated by the paired samples t test and are expressed as mean ± SD.
AUCglu0-3, area under the plasma concentrationetime curve from 0 h to 3 h for
plasma glucose; AUCglu0-3, area under the plasma concentrationetime curve from
0 h to 3 h for plasma insulin; Cglu0.5, plasma concentration of glucose at 0.5 h; Cins0.5,
plasma concentration of insulin at 0.5 h; FINS, fasting serum insulin concentration;
HOMA-IR: threshold value for insulin resistance; HOMA-IS: threshold value for
insulin secretion.

metformin transporters such as OCTs, MATEs and PMAT through

the above signaling, which in return alters the Pharmacokinetics of
metformin.
Although telmisartan is an anti-hypertension drug, it is recently
found to be an agent of insulin sensitivity proving. The pharma-
cological function of telmisartan on insulin sensitivity in murine
model is probably via PPARd or AMPK signals.26,27 In human trials,
it was demonstrated that telmisartan significant reduced insulin by
5.19% (in percent changes of insulin levels; 95%CI: 8.94%e1.43%)
and HOMA-IR by 15.34% (95%CI: 26.39%e4.28%)28 in hypertensive
patients. This effect was also observed in patients with obesity,
diabetes, impaired glucose tolerance, or metabolic syndrome.29
However, in our study, the FINS and HOMA-IR were not signifi-
cantly changed after the administration of telmisartan for 7
consecutive days. In addition, during OGTT, the AUC of insulin for
the entire 180-min test (although not significantly changed) or the
plasma concentration of insulin at 0.5 h (Cins0.5) was higher in the
group treated with metformin plus telmisartan than with placebo.
The lower insulin levels may related to glucose level which was
much lower in the group treated with metformin plus telmisartan,
as a result of decreased plasma concentration of metformin. The Fig. 2. The plasma concentrationetime curve of glucose (A) and insulin (B) during oral
regulation of glucose and insulin can be different between healthy glucose tolerance tests (OGTT). Plasma glucose and insulin of OGTT were determined
individuals and patients with insulin resistance, so that our study 2 h after the administration of metformin plus telmisartan or placebo in healthy
participants (n ¼ 15). Data are expressed as mean ± SD (n ¼ 15). *P < 0.05 (Metformin
observed a lower plasma insulin concentration in healthy vol-
plus telmisartan treatment vs. metformin plus placebo treatment).
unteets in which telmisartan coadministration increased the
plasma concentration of metformin. Although telmisartan have the
potential of decreasing systemic insulin, the dramatic change of diabetic patients. Third, whether metformin have the same effect
glucose concentration induced by metformin led to the fluctuation on Pharmacokinetics and Pharmacodynamics of telmisartan is also
of insulin. worthy to be illustrated.
Conclusive though the study is, there are some limitations. First, In summary, telmisartan decreased the systemic concentration
the in vitro inhibition studies are needed to verify whether telmi- and bioavailability of metformin, with the mechanism inconclusive.
sartan can decrease OCT3-and PMAT-mediated metformin trans- Although the influence of telmisartan on metformin pharmacoki-
porting. Second, the long-term use of telmisartan on the glucose netics was significant, the influence on the glucose-lowering effect
lowering effect of metformin should be investigated in the trial of was weak.

Please cite this article as: Wen J et al., The influence of telmisartan on metformin pharmacokinetics and pharmacodynamics, Journal of
Pharmacological Sciences, https://doi.org/10.1016/j.jphs.2018.11.007
 J. Wen et al. / Journal of Pharmacological Sciences xxx (xxxx) xxx
Conflict of interest
The authors declare no conflicts of interest.
Acknowledgments
This research was supported by grants from the National Key
Research and Development Program (No. 2016YFC0905000), Na-
tional Science Foundation (No. 81522048, 81573511, 81472802,
81273595) and Innovation Driven Project of Central South Univer-
sity (No.2016CX024).
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