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Contents lists available at ScienceDirect 56
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Journal of Pharmacological Sciences 59
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journal homepage: www.elsevier.com/locate/jphs 61
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Full Paper 64
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1 The influence of telmisartan on metformin pharmacokinetics and 66
2 67
3 pharmacodynamics 68
4 69
5 Q4 Jiagen Wen a, b, Meizi Zeng a, c, Zhaoqian Liu a, d, Honghao Zhou a, d, Heng Xu e, 70
6
Min Huang f, Wei Zhang a, d, * 71
7 72
a
8 Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China
b 73
School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
9 c 74
Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
10 d
Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China 75
11 e
Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Precision Medicine Key 76
12 Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
77
f
13 School of Pharmaceutical Science, Sun Yat-Sen University, GuangZhou, GuangDong, China
78
14 79
15 80
16 a r t i c l e i n f o a b s t r a c t 81
17 82
Article history: Metformin is the most widely used drug among type 2 diabetes mellitus patients. However, drug
18 83
Received 14 January 2018 interaction on metformin will influence its glucose-lowering effect or increase its side effect of lactic
19 Received in revised form 84
acidosis. In this study, a randomized, two-stage, crossover study was conducted to unveil the potential
20 1 November 2018 85
drug interaction between metformin and the anti-hypertension drug, telmisartan. Totally, 16 healthy
21 Accepted 19 November 2018
86
Available online xxx
Chinese male volunteers were enrolled. Blood samples from various time-points after drug adminstra-
22 tion were analyzed for metformin quantification. Oral glucose tolerance test (OGTT) was conducted 2 h 87
23 after metformin administration. The AUC0-12 and Cmax of metformin in subjects co-administrated with 88
Keywords:
24 telmisartan were significantly lower than with placebo. The geometric mean ratios (value of metformin 89
Telmisartan
25 Metformin plus telmisartan phase/value of metformin plus placebo phase) for Cmax and AUC0-12 is 0.7972 (90%CI: 90
26 Pharmacokinetics 0.7202e0.8824) and 0.8336 (90%CI: 0.7696e0.9028), respectively. Moreover, telmisartan co- 91
27 Pharmacodynamics administration significantly increased the plasma concentrations of both glucose and insulin at 0.5 h
92
28 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$min vs
93
29 60.20 ± 24.20 mIU/ml$min, P ¼ 0.037), though the AUC of glucose and insulin after OGTT showed no
94
significant difference. These findings suggested that telmisartan had a significant influence on the
30 95
Pharmacokinetics of metformin in healthy groups, though the influence on glucose-lowering effect was
31 96
moderate.
32 © 2018 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological 97
33 Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ 98
34 licenses/by-nc-nd/4.0/). 99
35 100
36 101
37 102
38 103
39 1. Introduction is often co-administrated with other types of anti-diabetic drugs.2 104
40 Moreover, a proportion of diabetic patients are vulnerable to 105
41 Metformin (1,1-dimethylbiguanide) is the most frequently pre- other diseases such as infection, hypertension, hyperlipemia, car- 106
42 scribed drug for the treatment of type 2 diabetes mellitus. It de- diovascular events and nephropathy, which means kinds of drugs 107
43 creases the blood glucose concentration mainly through inhibiting will be given to diabetic patients as well as anti-diabetic drugs.3e5 108
44 gastrointestinal glucose absorption and hepatic glucose production Therefore, drug interaction during anti-diabetic therapy should be 109
45 and increasing the glucose uptake and insulin sensitivity in mus- cautious. 110
46 cle.1 During the medication of type 2 diabetes mellitus, metformin Hypertension is the most common complication of diabetes 111
47 mellitus, affecting more than 10% of diabetic patients.6 Antihyper- 112
48 tensive agents telmisartan, one of Angiotensin II 1 (AT1) receptor 113
49 * Corresponding author. Department of Clinical Pharmacology, Xiangya Hospital, antagonists, is often prescribed to diabetic patients, not only 114
50 Central South University, ChangSha, 410078, China. Fax: þ86 0731 8235 4476. because it decrease blood pressure efficiently but also it is of great 115
51 E-mail address: yjsd2003@163.com (W. Zhang). merits in alleviating diabetic nephrotoxicity.7 As an oral 116
Peer review under responsibility of Japanese Pharmacological Society.
52 117
53 118
https://doi.org/10.1016/j.jphs.2018.11.007
54 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 119
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
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2 J. Wen et al. / Journal of Pharmacological Sciences xxx (xxxx) xxx

1 administration drug, telmisartan accumulate largely in liver and 2.3. Blood collection 66
2 have a inhibitory effect on CYP450 enzymes such as CYP2C8,8 67
3 CYP2C99 and CYP2J2.10 Furthermore, several studies demon- In each period, indwelling catheter was inserted in the forearm Q5 68
4 strated that telmisartan can inhibit the ABCG2-, ABCB1-, OAT1-and at 0 h (predose) on Day 7. To determine metformin concentrations 69
5 OCT2-mediated drug transporting.11,12 According to the studies of in the plasma, blood samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 70
6 human volunteers, telmisartan can interfere the metabolism of 3.5, 4, 6, 8, 10 and 12 h after the second dose of metformin. For OGTT 71
7 arachidonic acid8,9 and increase the systemic of rosuvastatin.11 analysis, blood samples were collected immediately before the 72
8 Although it is commonly used combined with metformin, there is ingestion of glucose and at 15, 30, 45, 60, 90, 120 and 180 min after 73
9 no reported study of the drug interaction between telmisartan and ingestion. Blood samples were centrifuged and separated. All 74
10 metformin. samples were frozen at 80  C pending assaying. 75
11 Therefore, in present study, a randomized, double-blind, two- 76
12 way crossover and placebo controlled trial was employed to 2.4. Metformin analysis 77
13 investigate the effects of telmisartan on the pharmacokinetics and 78
14 pharmacodynamics of metformin. The detection of metformin was performed on a Shimadzu LC- 79
15 2010C HPLC system (Kyoto, Japan) with autosampler and ultravio- 80
16 2. Materials and methods let detector. The Class-VP software (Shimadzu) was used for data 81
17 analysis and processing. Compounds was separated on a Hypersil 82
18 2.1. Subjects BDS C18 column (4.6 mm*200 mm, 5 mm particle size) with a 83
19 Phenomenex Security GuardTM guard column (Phenomenex, US) 84
20 Sixteen healthy male subjects (age 25 ± 4 years; height and quantified by UV detection at 232 nm. The mobile phase was 85
21 173.3 ± 5.5 cm; weight 64.5 ± 5.4 kg; BMI 21.42 ± 0.78; fasting composed of 0.1 M phosphate buffer (with 0.3% triethylamine and 86
22 plasma glucose 4.94 ± 0.31 mmol/l) were recruited in this study. 0.036% sodium dodecyl sulfate): Acetonitrile ¼ 25:75 (V: V), and 87
23 Exclusion criteria were anaemia (haemoglobin <12 g/dl), history of was delivered at a flow rate of 1.0 ml/min. Metformin was used as 88
24 drug abuse, symptomatic coronary heart disease, significant an external standard. Sample was prepared as the following pro- 89
25 elevation of hepatic enzyme levels (aspartate aminotransferase cedure: 200 ml of plasma were mixed with 400 ml of Acetonitrile in a 90
26 [AST] or alanine aminotransferase [ALT] > 60 IU/l), serum 1.5 ml plastic tube and the mixture was vortexed for 5 min. After 91
27 creatinine > 1.5 mg/dl, fasting plasma glucose > 6.1 mmol/L or centrifugation for 10 min at 13000 r/min, the supernatants were 92
28 presenting any one of the criteria for metabolic syndrome. Subjects transferred into an injection vial, and 20 ml was injected into the 93
29 who were consuming more than 2 alcoholic drinks (at one time) HPLC. The good linear relationship of metformin was obtained in 94
30 twice a week, smoking more than 10 cigarettes a day, or taking any the range of 25.0e5000 ng/ml, with regression equation Y ¼ e 95
31 medication were also excluded. 0.1022685 þ 1.08618325*X (r2 ¼ 0.99627). The limit of metformin 96
32 detection is 25.0 ng/mL. The intraday and interday coefficients of 97
33 2.2. Study design variation were <10%. The sample recovery range from 95% to 105% 98
34 and the RSD was 1.92%. 99
35 A randomized crossover study with two phases and a washout 100
36 period of 4 weeks was carried out. The study was approved by the 2.5. Glucose concentration analysis 101
37 Ethics Committee of Institute of Clinical Pharmacology, Central 102
38 South University (Project No: CTXY-140007-1) and registered in The pharmacodynamics of metformin was characterized by the 103
39 Chinese Clinical Trial Registry (ChiCTR-IPR-14005491). plasma insulin and blood glucose responses. Serum insulin and 104
40 All participants signed the informed consent before the clinical blood glucose concentrations were measured by fully automatic 105
41 trial. Once enrolled, participants were advised to maintain stable biochemical detector immediately after sampling. The plasma in- 106
42 activity levels (without periods of strenuous exercise) for 7 days sulin response was characterized by determining the fasting insulin 107
43 before the formal study. Approximately 3 days prior to the study, concentration (FINS), the threshold value for insulin resistance 108
44 subjects met with a dietitian to create a 3-day meal plan that (HOMA-IR) and the threshold value for insulin secretion (HOMA- 109
45 maintained carbohydrate intake at 200e250 g/day. The volunteers IS). The threshold value for insulin resistance (HOMA-IR) and the 110
46 recorded their food intake in a 3-day food diary. The last meal threshold value for insulin secretion (HOMA-IS) were calculated 111
47 before admission was eaten in the Clinical Trials Centre at Xiangya with the following equations: 112
48 Hospital. All subjects were divided into two groups (group one, 113
49 n ¼ 8; group two, n ¼ 8) randomly. The volunteers took 80 mg HOMA-IR¼FINS  FPG/22.5 114
50 telmisartan (Boehringer Ingelheim Pharma GmbH & Co. KG, Ger- 115
51 many) or placebo orally once daily at 08.00 h for 7 days. At 20.00 h HOMA-IS ¼ 20  FINS/(FPG-3.5) 116
52 on day 6, the participants received a 500 mg oral dose of metformin 117
53 (Shenzhen Neptunus Pharmaceutical. Co., Ltd, China). After an The blood glucose response was AUC0-3, maximum concentra- 118
54 overnight fast at 08.00 h on day 7, subjects were given another dose tion. The AUC values were calculated by the linear trapezoidal rule. 119
55 of 750 mg metformin (Shenzhen Neptunus Pharmaceutical. Co., 120
56 Ltd, China) together with telmisartan or placebo. Two hours after 2.6. Pharmacokinetics 121
57 metformin administration an oral glucose tolerance test (OGTT) 122
58 was immediately conducted following ingestion of a 75-g glucose The Pharmacokinetic parameters were calculated by non- 123
59 load (Chongqing Heping Pharmaceutical Co., Ltd, China). compartmental analysis using DAS 3.20. Maximum metformin 124
60 Carbohydrate-controlled meals were provided 5 h after the second concentration (Cmax) and the time of maximum concentration 125
61 dose of metformin. After a washing period of 4 weeks, all subjects (Tmax) were determined, and the area under the metformin 126
62 entered into the study of next phase. In the stage two, one partic- concentrationetime curves for the time period 0e12 h (AUC0-12) 127
63 ipant experienced vomiting after ingestion of 75 g glucose. The were calculated using the linear trapezoidal rule. The elimination 128
64 OGTT data of this participant was excluded, while his pharmaco- rate constant (ke) was estimated from the slope of the best-fit line 129
65 kinetic data of metformin was kept. determined by linear regression analysis of the log-transformed 130

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
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J. Wen et al. / Journal of Pharmacological Sciences xxx (xxxx) xxx 3

1 concentrationetime curve. The elimination half-life (t1/2) was then are shown in Fig. 2A and B. Only at 0.5 h since OGTT, telmisartan 66
2 calculated from the equation t1/2 ¼ ln (2)/ke. treatment significant increased plasma concentration of glucose 67
3 and insulin (7.64 ± 1.86 mmol/l$min vs 6.77 ± 0.83 mmol/l$min, 68
4 2.7. Statistical analysis P ¼ 0.040; 72.91 ± 31.98 mIU/ml$min and 60.20 ± 24.20 mIU/ 69
5 ml$min, P ¼ 0.037), but the AUC of glucose and insulin for the entire 70
6 Measurements from the same subjects after telmisartan or 180-min test concentrationetime show no difference 71
7 placebo treatment were compared using the paired samples t test. (18.81 ± 3.19 mmol/l$min and 17.64 ± 1.81 mmol/l$min, P ¼ 0.089; 72
8 Data were expressed as mean values ± standard deviation (SD). The 147.90 ± 73.87 mIU/ml$min and 131.81 ± 65.17 mIU/ml$min 73
9 data were analyzed using SPSS v.19.0 (IMB Corp., Armonk, NY, USA). P ¼ 0.167) (Table 2). 74
10 P < 0.05 was considered significant. The associated drugedrug 75
11 interaction was assessed based on the 90% CIs of geometric mean 4. Discussion 76
12 ratios (metformin þ telmisartan to metformin þ placebo) for the 77
13 primary pharmacokinetic parameters (Cmax and AUC0-12). It was Metformin is a cationic drug and exerts the glucose-lowering 78
14 concluded that a significant pharmacokinetic interaction existed effect after oral administration. The oral absorption and hepatic 79
15 between the two drugs if the 90% CI values did not fall within the uptake of metformin are mediated possibly by organic cation 80
16 range of 0.80e1.25.13 transporters, whereas its excretion is mainly via renal drug trans- 81
17 porters OCT2 and MATEs.15 Drug interactions upon these trans- 82
18 3. Results porters can have a special influence on metformin PK. For example, 83
19 MATEs or OCT2 inhibitors, ondansetron16 and rabeprazole,17 can 84
20 3.1. Metformin pharmacokinetics increase the plasma concentration of metformin. Although telmi- 85
21 sartan was founded with a moderate effect of OCT2 inhibiting, the 86
22 The plasma concentrationetime profiles of metformin com- coadministration of telmisartan can decrease the plasma concen- 87
23 bined with telmisartan or placebo were shown in Fig. 1 and the tration of metformin. In particular, the geometric mean ratios of 88
24 parameters of metformin were shown in Table 1. The AUC0-12 and metformin plus telmisartan to metformin for Cmax and AUC0-12 are 89
25 Cmax of metformin mono-administration were consistent with the 0.7972 (90% CI: 0.7202e0.8824) and 0.8336 (90% CI: 90
26 previous studies.14 As shown in Table 1, the Cmax values and AUC0-12 0.7696e0.9028). The ratios fall out of the range of 0.8e1.25, which 91
27 of metformin significantly decreased by 20.8% (1156.31 ± 373.62 vs means a possible pharmacokinetic interaction between the two 92
28 1459.32 ± 527.68, P ¼ 0.001) and 17.6% (5379.26 ± 1713.50 vs drugs. Considering that the effects of telmisartan is lowering 93
29 6524.73 ± 2597.50, P ¼ 0.004), respectively, when co-administrated metformin plasma concentration, the role of telmisartan on met- 94
30 with telmisartan. However, telmisartan co-administration did not formin may not depend on renal transporters OCT2 and MATEs. 95
31 significantly change the parameter of Tmax and T1/2. The geometric As an oral administration drug, the absorption of telmisartan is 96
32 mean ratios of metformin plus telmisartan to metformin for Cmax mainly through intestine, with a bioavailability of 40e60%.18 Un- 97
33 and AUC0-12 is 0.7972 (90% CI: 0.7202e0.8825) and 0.8336 (90% CI: like most kinds of drug, less than 1% of telmisartan was eliminated 98
34 0.7696e0.9028), which fall out of the range of 0.8e1.25. via kidney and most of the drug were excreted through feces in its 99
35 original form.18,19 Because telmisartan have low water-solubility, 100
36 3.2. Metformin pharmacodynamics there will be a maximum concentration in gastrointestinal tracts. 101
37 The observed decrease in plasma levels of metformin may result in 102
38 Healthy volunteers (n ¼ 15) underwent oral glucose tolerance the direct inhibition of telmisartan on metformin absorption from 103
39 tests (OGTTs) after receiving two doses of metformin in combina- the gastrointestinal tract. Studies have indicated the inhibition of 104
40 tion with placebo or telmisartan. The FINS, HOMA-IR and HOMA-IS OCT1 decreased metformin hepatic uptake,20 and the OCT2 inhi- 105
41 between the two treatment were not significant different (Table 2). bition by rabeprazole reduced its kidney elimination resulting in 106
42 The plasma glucose/insulin concentrationetime curves after OGTTs the increase of its systemic concentration.17 OCT3 and PMAT 107
43 localized on the luminal side of intestinal epithelial cells, respon- 108
44 sible for metformin absorption.21,22 Although no investigation of 109
45 telmisartan on OCT3 or PMAT were given, possible it is that tel- 110
46 misartan also have an inhibitory effect on OCT3-or PMAT- 111
47 mediated metformin absorption. Also, the protein binding ratio 112
48 of telmisartan is as high as 99.5%, which means the free form of 113
49 telmisartan in plasma is of quite low level. Thus, it is unlike tel- 114
50 misartan have the ability of inhibiting metformin hepatic uptake 115
51 or renal excretion. 116
52 Although the protein binding ratio of telmisartan is high, nearly 117
53 none of metformin binds to plasma albumin. Thus, it is impossible 118
54 that telmisartan alter the metformin concentration through 119
55 competitive or incompetitive binding to albumin. Moreover, the 120
56 majority of metformin after absorption is in its natural form, which 121
57 functions in glucose lowering effect. It was reported that telmi- 122
58 sartan had inhibitory effect on CYP2C8, CYP2C9 and CYP2J2810. 123
59 However, it will not affect the Pharmacokinetics of metformin 124
60 through inhibiting metabolic enzymes. At present, a number of 125
61 studies demonstrated that telmisartan can act as a partial agonist of 126
62 peroxisome proliferator-activated receptor-gamma (PPARg) and 127
Fig. 1. The plasma concentrationetime curve of metformin. Metformin concentrations
63
were measured after the second dose of metformin. Data are expressed as mean ± SD
activate Akt/GSK-3b and AMPK.23e25 As a drug of long-term use, it 128
64 (n ¼ 16). *P < 0.05 (Metformin plus telmisartan treatment vs.metformin plus placebo is also hypothesized that telmisartan may induce the expression of 129
65 treatment). metformin transporters such as OCTs, MATEs and PMAT through 130

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
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4 J. Wen et al. / Journal of Pharmacological Sciences xxx (xxxx) xxx

1 Table 1 66
2 Pharmacokinetic parameters of metformin in healthy participants (n ¼ 16) after telmisartan and placebo treatment. 67
3 PK parameter MþT M p Geometric Mean Ratio (M þ T)/T 68
4 Ratio 90% CI
69
5 70
Cmax (ng/mL) 1156.31 ± 373.62 1459.32 ± 527.68 0.001 0.8336 0.7696e0.9028
6 71
AUC0-12 (ng/mL$h) 5379.26 ± 1713.50 6524.73 ± 2597.50 0.004 0.7972 0.7202e0.8825
7 Tmax (h) 1.34 ± 0.85 1.41 ± 0.66 0.787 0.9050 0.6529e1.2546 72
8 T1/2 (h) 2.94 ± 1.72 2.41 ± 1.48 0.238 1.2055 0.9073e1.6015 73
9 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
74
10 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 75
11 telmisartan. 76
12 77
13 78
Table 2
14 79
The oral glucose tolerance test (OGTT) parameters of metformin after telmisartan
15 and placebo treatment in healthy participants (n ¼ 15).
80
16 81
Parameters MþT M p
17 82
18 AUCglu0-3 (mmol/L∙min) 18.81 ± 3.19 17.64 ± 1.81 0.089 83
19 AUCins0-3 (mIU/ml∙min) 147.90 ± 73.87 131.81 ± 65.17 0.167 84
Cglu0.5 (mmol/L) 7.64 ± 1.86 6.77 ± 0.83 0.040
20 Cins0.5 (mIU/ml) 72.91 ± 31.98 60.20 ± 24.20 0.037
85
21 FINS (mIU/ml) 6.39 ± 4.85 4.96 ± 5.11 0.130 86
22 HOMA-IR 1.44 ± 1.131 1.07 ± 1.09 0.071 87
23 HOMA-IS 85.15 ± 59.82 79.27 ± 81.56 0.720 88
24 Data were evaluated by the paired samples t test and are expressed as mean ± SD. 89
25 AUCglu0-3, area under the plasma concentrationetime curve from 0 h to 3 h for 90
26 plasma glucose; AUCglu0-3, area under the plasma concentrationetime curve from 91
0 h to 3 h for plasma insulin; Cglu0.5, plasma concentration of glucose at 0.5 h; Cins0.5,
27 plasma concentration of insulin at 0.5 h; FINS, fasting serum insulin concentration;
92
28 HOMA-IR: threshold value for insulin resistance; HOMA-IS: threshold value for 93
29 insulin secretion. 94
30 95
31 96
32 the above signaling, which in return alters the Pharmacokinetics of 97
33 metformin. 98
34 Although telmisartan is an anti-hypertension drug, it is recently 99
35 found to be an agent of insulin sensitivity proving. The pharma- 100
36 cological function of telmisartan on insulin sensitivity in murine 101
37 model is probably via PPARd or AMPK signals.26,27 In human trials, 102
38 it was demonstrated that telmisartan significant reduced insulin by 103
39 5.19% (in percent changes of insulin levels; 95%CI: 8.94%e1.43%) 104
40 and HOMA-IR by 15.34% (95%CI: 26.39%e4.28%)28 in hypertensive 105
41 patients. This effect was also observed in patients with obesity, 106
42 diabetes, impaired glucose tolerance, or metabolic syndrome.29 107
43 However, in our study, the FINS and HOMA-IR were not signifi- 108
44 cantly changed after the administration of telmisartan for 7 109
45 consecutive days. In addition, during OGTT, the AUC of insulin for 110
46 the entire 180-min test (although not significantly changed) or the 111
47 plasma concentration of insulin at 0.5 h (Cins0.5) was higher in the 112
48 group treated with metformin plus telmisartan than with placebo. 113
49 The lower insulin levels may related to glucose level which was 114
50 much lower in the group treated with metformin plus telmisartan, 115
51 as a result of decreased plasma concentration of metformin. The 116
52 regulation of glucose and insulin can be different between healthy 117
Fig. 2. The plasma concentrationetime curve of glucose (A) and insulin (B) during oral
53 individuals and patients with insulin resistance, so that our study glucose tolerance tests (OGTT). Plasma glucose and insulin of OGTT were determined 118
54 observed a lower plasma insulin concentration in healthy vol- 2 h after the administration of metformin plus telmisartan or placebo in healthy 119
55 unteets in which telmisartan coadministration increased the participants (n ¼ 15). Data are expressed as mean ± SD (n ¼ 15). *P < 0.05 (Metformin 120
plasma concentration of metformin. Although telmisartan have the plus telmisartan treatment vs. metformin plus placebo treatment).
56 121
57 potential of decreasing systemic insulin, the dramatic change of 122
58 glucose concentration induced by metformin led to the fluctuation 123
of insulin. diabetic patients. Third, whether metformin have the same effect
59 124
Conclusive though the study is, there are some limitations. First, on PK and PD of telmisartan is also worthy to be illustrated.
60 125
the in vitro inhibition studies are needed to verify whether telmi- In summary, telmisartan decreased the systemic concentration
61 126
sartan can decrease OCT3-and PMAT-mediated metformin trans- and bioavailability of metformin, with the mechanism inconclusive.
62 127
porting. Second, the long-term use of telmisartan on the glucose Although the influence of telmisartan on metformin PK was sig-
63 128
lowering effect of metformin should be investigated in the trial of nificant, the influence on the glucose-lowering effect was weak.
64 129
65 130

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
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J. Wen et al. / Journal of Pharmacological Sciences xxx (xxxx) xxx 5

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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