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The influence of telmisartan on metformin pharmacokinetics and pharmacodynamics
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The influence of telmisartan on metformin pharmacokinetics and pharmacodynamics Q4
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 School of Pharmacy, Anhui Medical University, Hefei, Anhui, China 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 b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 January 2018 Received in revised form 1 November 2018 Accepted 19 November 2018 Available online xxx
Metformin is the most widely used drug among type 2 diabetes mellitus patients. However, drug interaction on metformin will influence its glucose-lowering effect or increase its side effect of lactic acidosis. In this study, a randomized, two-stage, crossover study was conducted to unveil the potential drug interaction between metformin and the anti-hypertension drug, telmisartan. Totally, 16 healthy Chinese male volunteers were enrolled. Blood samples from various time-points after drug adminstration 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 telmisartan were significantly lower than with placebo. The geometric mean ratios (value of metformin plus telmisartan phase/value of metformin plus placebo phase) for Cmax and AUC0-12 is 0.7972 (90%CI: 0.7202e0.8824) and 0.8336 (90%CI: 0.7696e0.9028), respectively. Moreover, telmisartan coadministration significantly increased the plasma concentrations of both glucose and insulin at 0.5 h 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/).
Keywords: Telmisartan Metformin Pharmacokinetics Pharmacodynamics Drugedrug interaction
1. Introduction Metformin (1,1-dimethylbiguanide) is the most frequently prescribed drug for the treatment of type 2 diabetes mellitus. It decreases the blood glucose concentration mainly through inhibiting gastrointestinal glucose absorption and hepatic glucose production and increasing the glucose uptake and insulin sensitivity in muscle.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: [email protected] (W. Zhang). Peer review under responsibility of Japanese Pharmacological Society.
is often co-administrated with other types of anti-diabetic drugs.2 Moreover, a proportion of diabetic patients are vulnerable to other diseases such as infection, hypertension, hyperlipemia, cardiovascular events and nephropathy, which means kinds of drugs will be given to diabetic patients as well as anti-diabetic drugs.3e5 Therefore, 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 Antihypertensive 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
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administration drug, telmisartan accumulate largely in liver and have a inhibitory effect on CYP450 enzymes such as CYP2C8,8 CYP2C99 and CYP2J2.10 Furthermore, several studies demonstrated 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 of rosuvastatin.11 Although it is commonly used combined with metformin, there is no reported study of the drug interaction between telmisartan and metformin. Therefore, in present study, a randomized, double-blind, twoway 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, Germany) 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 participant experienced vomiting after ingestion of 75 g glucose. The OGTT data of this participant was excluded, while his pharmacokinetic data of metformin was kept.
2.3. Blood collection In each period, indwelling catheter was inserted in the forearm Q5 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 analysis The detection of metformin was performed on a Shimadzu LC2010C HPLC system (Kyoto, Japan) with autosampler and ultraviolet 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 procedure: 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 regression equation Y ¼ e 0.1022685 þ 1.08618325*X (r2 ¼ 0.99627). The limit of metformin detection is 25.0 ng/mL. The intraday and interday coefficients of variation were <10%. The sample recovery range from 95% to 105% and the RSD was 1.92%. 2.5. Glucose 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 insulin 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 (HOMAIS). 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 concentration. The AUC values were calculated by the linear trapezoidal rule. 2.6. Pharmacokinetics The Pharmacokinetic parameters were calculated by noncompartmental 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
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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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. Metformin pharmacokinetics The plasma concentrationetime profiles of metformin combined 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. Metformin pharmacodynamics Healthy volunteers (n ¼ 15) underwent oral glucose tolerance tests (OGTTs) after receiving two doses of metformin in combination with placebo or telmisartan. The FINS, HOMA-IR and HOMA-IS between the two treatment were not significant different (Table 2). The plasma glucose/insulin concentrationetime curves after OGTTs
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).
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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 show 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 transporters OCT2 and MATEs.15 Drug interactions upon these transporters can have a special influence on metformin PK. For example, MATEs or OCT2 inhibitors, ondansetron16 and rabeprazole,17 can increase the plasma concentration of metformin. Although telmisartan was founded with a moderate effect of OCT2 inhibiting, the coadministration of telmisartan 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 pharmacokinetic 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 Unlike 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 have 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 inhibition 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, responsible for metformin absorption.21,22 Although no investigation of telmisartan on OCT3 or PMAT were given, possible it is that telmisartan also have an inhibitory effect on OCT3-or PMATmediated 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 telmisartan have 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 alter 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 telmisartan 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 metformin transporters such as OCTs, MATEs and PMAT through
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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Table 1 Pharmacokinetic parameters of metformin in healthy participants (n ¼ 16) after telmisartan and placebo treatment. PK parameter
Cmax (ng/mL) AUC0-12 (ng/mL$h) Tmax (h) T1/2 (h)
MþT
M
1156.31 ± 373.62 5379.26 ± 1713.50 1.34 ± 0.85 2.94 ± 1.72
p
1459.32 ± 527.68 6524.73 ± 2597.50 1.41 ± 0.66 2.41 ± 1.48
0.001 0.004 0.787 0.238
Geometric Mean Ratio (M þ T)/T Ratio
90% CI
0.8336 0.7972 0.9050 1.2055
0.7696e0.9028 0.7202e0.8825 0.6529e1.2546 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) AUCins0-3 (mIU/ml∙min) Cglu0.5 (mmol/L) Cins0.5 (mIU/ml) FINS (mIU/ml) HOMA-IR HOMA-IS
18.81 ± 3.19 147.90 ± 73.87 7.64 ± 1.86 72.91 ± 31.98 6.39 ± 4.85 1.44 ± 1.131 85.15 ± 59.82
17.64 ± 1.81 131.81 ± 65.17 6.77 ± 0.83 60.20 ± 24.20 4.96 ± 5.11 1.07 ± 1.09 79.27 ± 81.56
0.089 0.167 0.040 0.037 0.130 0.071 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.
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 pharmacological 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 significantly 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 regulation of glucose and insulin can be different between healthy individuals and patients with insulin resistance, so that our study observed a lower plasma insulin concentration in healthy volunteets in which telmisartan coadministration increased the plasma concentration of metformin. Although telmisartan have the potential of decreasing systemic insulin, the dramatic change of glucose concentration induced by metformin led to the fluctuation of insulin. Conclusive though the study is, there are some limitations. First, the in vitro inhibition studies are needed to verify whether telmisartan can decrease OCT3-and PMAT-mediated metformin transporting. Second, the long-term use of telmisartan on the glucose lowering effect of metformin should be investigated in the trial of
Fig. 2. The plasma concentrationetime curve of glucose (A) and insulin (B) during oral glucose tolerance tests (OGTT). Plasma glucose and insulin of OGTT were determined 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 plus telmisartan treatment vs. metformin plus placebo treatment).
diabetic patients. Third, whether metformin have the same effect on PK and PD of telmisartan is also worthy to be illustrated. In summary, telmisartan decreased the systemic concentration and bioavailability of metformin, with the mechanism inconclusive. Although the influence of telmisartan on metformin PK was significant, the influence on the glucose-lowering effect 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
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Conflict of interest The authors declare none of conflicting interests.
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Acknowledgments This research was supported by grants from the National Key Research and Development Program (No. 2016YFC0905000), National Science Foundation (No. 81522048, 81573511, 81472802, 81273595) and Innovation Driven Project of Central South University (No.2016CX024). References
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The influence of telmisartan on metformin pharmacokinetics and pharmacodynamics Q4
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 School of Pharmacy, Anhui Medical University, Hefei, Anhui, China 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 b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 January 2018 Received in revised form 1 November 2018 Accepted 19 November 2018 Available online xxx
Metformin is the most widely used drug among type 2 diabetes mellitus patients. However, drug interaction on metformin will influence its glucose-lowering effect or increase its side effect of lactic acidosis. In this study, a randomized, two-stage, crossover study was conducted to unveil the potential drug interaction between metformin and the anti-hypertension drug, telmisartan. Totally, 16 healthy Chinese male volunteers were enrolled. Blood samples from various time-points after drug adminstration 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 telmisartan were significantly lower than with placebo. The geometric mean ratios (value of metformin plus telmisartan phase/value of metformin plus placebo phase) for Cmax and AUC0-12 is 0.7972 (90%CI: 0.7202e0.8824) and 0.8336 (90%CI: 0.7696e0.9028), respectively. Moreover, telmisartan coadministration significantly increased the plasma concentrations of both glucose and insulin at 0.5 h 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/).
Keywords: Telmisartan Metformin Pharmacokinetics Pharmacodynamics Drugedrug interaction
1. Introduction Metformin (1,1-dimethylbiguanide) is the most frequently prescribed drug for the treatment of type 2 diabetes mellitus. It decreases the blood glucose concentration mainly through inhibiting gastrointestinal glucose absorption and hepatic glucose production and increasing the glucose uptake and insulin sensitivity in muscle.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: [email protected] (W. Zhang). Peer review under responsibility of Japanese Pharmacological Society.
is often co-administrated with other types of anti-diabetic drugs.2 Moreover, a proportion of diabetic patients are vulnerable to other diseases such as infection, hypertension, hyperlipemia, cardiovascular events and nephropathy, which means kinds of drugs will be given to diabetic patients as well as anti-diabetic drugs.3e5 Therefore, 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 Antihypertensive 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
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administration drug, telmisartan accumulate largely in liver and have a inhibitory effect on CYP450 enzymes such as CYP2C8,8 CYP2C99 and CYP2J2.10 Furthermore, several studies demonstrated 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 of rosuvastatin.11 Although it is commonly used combined with metformin, there is no reported study of the drug interaction between telmisartan and metformin. Therefore, in present study, a randomized, double-blind, twoway 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, Germany) 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 participant experienced vomiting after ingestion of 75 g glucose. The OGTT data of this participant was excluded, while his pharmacokinetic data of metformin was kept.
2.3. Blood collection In each period, indwelling catheter was inserted in the forearm Q5 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 analysis The detection of metformin was performed on a Shimadzu LC2010C HPLC system (Kyoto, Japan) with autosampler and ultraviolet 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 procedure: 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 regression equation Y ¼ e 0.1022685 þ 1.08618325*X (r2 ¼ 0.99627). The limit of metformin detection is 25.0 ng/mL. The intraday and interday coefficients of variation were <10%. The sample recovery range from 95% to 105% and the RSD was 1.92%. 2.5. Glucose 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 insulin 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 (HOMAIS). 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 concentration. The AUC values were calculated by the linear trapezoidal rule. 2.6. Pharmacokinetics The Pharmacokinetic parameters were calculated by noncompartmental 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
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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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. Metformin pharmacokinetics The plasma concentrationetime profiles of metformin combined 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. Metformin pharmacodynamics Healthy volunteers (n ¼ 15) underwent oral glucose tolerance tests (OGTTs) after receiving two doses of metformin in combination with placebo or telmisartan. The FINS, HOMA-IR and HOMA-IS between the two treatment were not significant different (Table 2). The plasma glucose/insulin concentrationetime curves after OGTTs
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).
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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$min, P ¼ 0.037), but the AUC of glucose and insulin for the entire 180-min test concentrationetime show no difference (18.81 ± 3.19 mmol/l$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 transporters OCT2 and MATEs.15 Drug interactions upon these transporters can have a special influence on metformin PK. For example, MATEs or OCT2 inhibitors, ondansetron16 and rabeprazole,17 can increase the plasma concentration of metformin. Although telmisartan was founded with a moderate effect of OCT2 inhibiting, the coadministration of telmisartan 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 pharmacokinetic 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 Unlike 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 have 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 inhibition 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, responsible for metformin absorption.21,22 Although no investigation of telmisartan on OCT3 or PMAT were given, possible it is that telmisartan also have an inhibitory effect on OCT3-or PMATmediated 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 telmisartan have 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 alter 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 telmisartan 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 metformin transporters such as OCTs, MATEs and PMAT through
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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Table 1 Pharmacokinetic parameters of metformin in healthy participants (n ¼ 16) after telmisartan and placebo treatment. PK parameter
Cmax (ng/mL) AUC0-12 (ng/mL$h) Tmax (h) T1/2 (h)
MþT
M
1156.31 ± 373.62 5379.26 ± 1713.50 1.34 ± 0.85 2.94 ± 1.72
p
1459.32 ± 527.68 6524.73 ± 2597.50 1.41 ± 0.66 2.41 ± 1.48
0.001 0.004 0.787 0.238
Geometric Mean Ratio (M þ T)/T Ratio
90% CI
0.8336 0.7972 0.9050 1.2055
0.7696e0.9028 0.7202e0.8825 0.6529e1.2546 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) AUCins0-3 (mIU/ml∙min) Cglu0.5 (mmol/L) Cins0.5 (mIU/ml) FINS (mIU/ml) HOMA-IR HOMA-IS
18.81 ± 3.19 147.90 ± 73.87 7.64 ± 1.86 72.91 ± 31.98 6.39 ± 4.85 1.44 ± 1.131 85.15 ± 59.82
17.64 ± 1.81 131.81 ± 65.17 6.77 ± 0.83 60.20 ± 24.20 4.96 ± 5.11 1.07 ± 1.09 79.27 ± 81.56
0.089 0.167 0.040 0.037 0.130 0.071 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.
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 pharmacological 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 significantly 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 regulation of glucose and insulin can be different between healthy individuals and patients with insulin resistance, so that our study observed a lower plasma insulin concentration in healthy volunteets in which telmisartan coadministration increased the plasma concentration of metformin. Although telmisartan have the potential of decreasing systemic insulin, the dramatic change of glucose concentration induced by metformin led to the fluctuation of insulin. Conclusive though the study is, there are some limitations. First, the in vitro inhibition studies are needed to verify whether telmisartan can decrease OCT3-and PMAT-mediated metformin transporting. Second, the long-term use of telmisartan on the glucose lowering effect of metformin should be investigated in the trial of
Fig. 2. The plasma concentrationetime curve of glucose (A) and insulin (B) during oral glucose tolerance tests (OGTT). Plasma glucose and insulin of OGTT were determined 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 plus telmisartan treatment vs. metformin plus placebo treatment).
diabetic patients. Third, whether metformin have the same effect on PK and PD of telmisartan is also worthy to be illustrated. In summary, telmisartan decreased the systemic concentration and bioavailability of metformin, with the mechanism inconclusive. Although the influence of telmisartan on metformin PK was significant, the influence on the glucose-lowering effect 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
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Conflict of interest The authors declare none of conflicting interests.
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Acknowledgments This research was supported by grants from the National Key Research and Development Program (No. 2016YFC0905000), National Science Foundation (No. 81522048, 81573511, 81472802, 81273595) and Innovation Driven Project of Central South University (No.2016CX024). References
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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
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