Concentrations Of Telmisartan Research Articles

Pharmacokinetic and bioequivalence study of Telzap® in comparison with Mikardis® in healthy subjects after single administrationl

Introduction. Telmisartan is widely used in clinical practice during hypertension treatment. It is a specific angiotensin II receptor antagonist (type AT1), effective at oral intake, A bioequivalence study of Telzap® and Mikardis® was conducted with 60 volunteers.Aim. The purpose of the bioequivalence trial was a comparative study of the pharmacokinetics and evidence of the bioequivalence of Mikardis® (telmisartan, tablets 80 mg, Boehringer Ingelheim International GmbH, Germany) and Telzap® (telmisartan, tablets 80 mg, Zentiva KS company, Czech Republic) in healthy volunteers after a single administration under fasting.Materials and methods. To prove bioequivalence, an open label, comparative, randomized, crossover four-period replicate single-center clinical trial was conducted. The concentrations of telmisartan in plasma samples were determined by a validated HPLC-MS/MS method. A pharmacokinetic and statistical analysis was performed and confidence intervals for the pharmacokinetic parameters Cmax and AUC0-72 were calculated.Results and discussion. It can be concluded that the studied formulations are bioequivalent in terms of pharmacokinetic parameters of test and reference drug. All 90 % confidence intervals of were within the bioequivalence range of 80–125 % for AUC0-72 and 73,07–136,85 % for Cmax.Conclusion. Thus, according to the criteria used in the study, the formulations are proved to be bioequivalent.

Comparing the Neuroprotective Effects of Telmisartan, Perindopril, and Nebivolol Against Lipopolysaccharide-Induced Injury in Neuron-Like Cells.

The effect of antihypertensive drugs, especially drugs modulating the renin-angiotensin-aldosterone-system (RAAS), on neurodegenerative diseases still needs to be investigated. This study aimed to compare the effects of three different antihypertensive drugs (telmisartan, perindopril, and nebivolol) on neuroprotection and acetylcholine (ACh) levels against lipopolysaccharide (LPS)-induced injury in a differentiated SH-SY5Y cell line. Cells were treated with retinoic acid for differentiation to a neuronal phenotype. LPS 20 (μg/mL) was applied to the cells for one hour. Then, the cells were treated with 1, 5, and 10 µg/mL concentrations of telmisartan, perindopril, and nebivolol separately for 24 hours, except for the control and LPS alone groups. Cell viability was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. ACh levels were analyzed using an enzyme immunosorbent assay in the culture medium. Tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) expressions were evaluated using western blot analysis. Telmisartan demonstrated the highest cell viability against LPS-induced injury, whereas the protective effect of perindopril was moderate. Nebivolol showed no neuroprotective effect. The protective effect of 10-µg/mL telmisartan was superior to 10 µg/mL perindopril (p=0.006), 5 µg/mL perindopril (p=0.001), 1 µg/mL perindopril (p=0.001), and 1, 5, and 10 µg/mL nebivolol (p<0.001). Among all the study drugs, only telmisartan provided a statistically significant increase in ACh levels after LPS-induced injury. Additionally, the administration of telmisartan provided a concentration-dependent reduction in TNF-α, IL-1β, and NFκB expression against LPS-induced neuroinflammation. These findings suggest that telmisartan has a superior neuroprotective effect against LPS-induced injury in neuron-like cells compared with both perindopril and nebivolol.

Experimental study on the construction of telmisartan/collagen/polycaprolactone nerve conduit and its repair effect on rat sciatic nerve defect

To construction the telmisartan/collagen/polycaprolactone (PCL) nerve conduit and assess its effect on repairing sciatic nerve defect in rats. The 60% collagen/hexafluoroisopropanol (HFIP) solution and 40% PCL/HFIP solution were prepared and mixed (collagen/PCL solution). Then the 0, 5, 10, and 20 mg of telmisartan were mixed with the 10 mL collagen/PCL solution, respectively. Telmisartan/collagen/PCL nerve conduits were fabricated via high voltage electrospinning technology. The structure of nerve conduit before and after crosslinking was observed by using scanning electron microscope (SEM). The drug release efficiency was detected by in vitro sustained release method. RAW264.7 cells were cultured with lipopolysaccharide to induce inflammation, and then co-cultured with nerve conduits loaded with different concentrations of telmisartan for 24 hours. The mRNA expressions of inducible nitric oxide synthase (iNOS) and Arginase 1 (Arg-1) were detected by using real-time fluorescence quantitative PCR. Forty adult Wistar rats were randomly divided into 4 groups ( n=10). After preparing 15-mm-long sciatic nerve defect, the defect was repaired by cross-linked nerve conduits loaded with 0, 5, 10, and 20 mg telmisartan in groups A, B, C, and D, respectively. After operation, the general condition of rats was observed after operation; the sciatic function index (SFI) was tested; the bridging between the nerve conduit and sciatic nerve, and the integrity of nerve conduit were observed; the tissue growth in nerve conduit and material degradation were observed by HE staining; the expressions of CD86 (M1 macrophage marker), CD206 (M2 macrophage marker), myelin basic protein (MBP), and myelin protein 0 (P0) in new tissues were also observed by immunohistochemical staining; the expressions of neurofilament 200 (NF-200) and S-100β in new tissues were assessed by immunofluorescence staining. The general observation showed that the inner diameter of the nerve conduit was 1.8 mm and the outer diameter was 2.0 mm. After cross-linking by genipin, the nanofiber became thicker and denser. The drug release test showed that the telmisartan loaded nerve conduit could be released gradually. With the increase of telmisartan content in nerve conduit, the iNOS mRNA expression decreased and the Arg-1 mRNA expression increased; and the differences between 20 mg group and other groups were significant ( P<0.05). In vivo experiment showed that all animals in each group survived until the completion of the experiment. The SFI was significantly higher in groups C and D than in groups A and B at different time points ( P<0.05) and in group D than in group C at 6 months after operation ( P<0.05). HE staining showed that there were significantly more new tissues in the middle of the nerve conduit in group D after operation than in other groups. Immunohistochemical staining showed that CD86 and CD206 stainings were positive in each group at 1 month after operation, among which group D had the lowest positive rate of CD86 and the highest positive rate of CD206, and there were significant differences in the positive rate of CD206 between group D and groups A, B, and C ( P<0.05); the MBP and P0 stainings were positive in groups C and D at 6 months, and the positive rate in group D was significantly higher than that in group C ( P<0.05). Immunofluorescence staining showed that the NF-200 and S-100β expressions in group D were significantly higher than those in other groups. Telmisartan/collagen/PLC nerve conduit can promote the sciatic nerve defect repair in rats through promoting the polarization of M1 macrophages to M2 macrophages, and the nerve conduit loaded with20 mg telmisartan has the most significant effect.

Bioequivalence Study of Two Formulations of Telmisartan 40 mg Tablets in Healthy Adult Bangladeshi Subjects under Fasting Conditions

Background: Telmisartan is a highly variable drug which is used to treat hypertension. This study compared to compare the bioavailability of two 40 mg Telmisartan tablets in adult and healthy Bangladeshi subjects. Materials and Method: This study was open label, randomized, laboratory blind, single dose, three periods, two treatments, three-sequence, partial-replicate, crossover and comparative oral bioavailability study. In this study, 18 Bangladeshi subjects were enrolled and 17 subjects were completed. Serial blood samples were collected up to 96 hours following drug administration. By using Liquid Chromatography Mass Spectrometry (LC-MS/MS) method, plasma concentrations of Telmisartan were determined. Results: The two formulations of Telmisartan were considered bioequivalent if 90% Confidence Interval (CI) fall within the range of 80.00% - 125.00% for AUC parameters and reference-scaled-average bioequivalence of 69.84% - 143.19% for Cmax. The 90% Confidence Interval for Cmax, AUC0-t & AUC0-∞ was found 84.88% - 107.79%, 89.76% - 109.55%, and 91.20% - 114.52%, respectively. Conclusion: According to rate and extent of absorption with the single dose of Reference Product (R): Micardis® 40 mg Tablet, under fasting conditions, a single dose of Telmisartan 40 mg Tablet is bioequivalent.

Telmisartan Inhibits the NLRP3 Inflammasome by Activating the PI3K Pathway in Neural Stem Cells Injured by Oxygen-Glucose Deprivation.

Angiotensin II receptor blockers (ARBs) have been shown to exert neuroprotective effects by suppressing inflammatory and apoptotic responses. In the present study, the effects of the ARB telmisartan on the NLRP3 inflammasome induced by oxygen-glucose deprivation (OGD) in neural stem cells (NSCs) were investigated, as well as their possible association with the activation of the PI3K pathway. Cultured NSCs were treated with different concentrations of telmisartan and subjected to various durations of OGD. Cell counting, lactate dehydrogenase, bromodeoxyuridine, and colony-forming unit assays were performed to measure cell viability and proliferation. In addition, the activity of intracellular signaling pathways associated with the PI3K pathway and NLRP3 inflammasome was evaluated. Telmisartan alone did not affect NSCs up to a concentration of 10μM under normal conditions but showed toxicity at a concentration of 100μM. Moreover, OGD reduced the viability of NSCs in a time-dependent manner. Nevertheless, treatment with telmisartan increased the viability and proliferation of OGD-injured NSCs. Furthermore, telmisartan promoted the expression of survival-related proteins and mRNA while inhibiting the expression of death-related proteins induced by OGD. In particular, telmisartan attenuated OGD-dependent expression of the NLRP3 inflammasome and its related signaling proteins. These beneficial effects of telmisartan were blocked by a PI3K inhibitor. Together, these results indicate that telmisartan attenuated the activation of the NLRP3 inflammasome by triggering the PI3K pathway, thereby contributing to neuroprotection.

Simultaneous Determination of Telmisartan and Pitavastatin Calcium in Intestinal Perfusate by HPLC: Application to Intestinal Absorption Interaction Study.

Hypertension and hypercholesterolemia are two main physiological risk factors of cardiovascular disease, and commonly occur in combination. Multicompound combination therapy is rational for the treatment of concurrent hypertension and hypercholesterolemia, while telmisartan and pitavastatin calcium can be used as a potential drug combination. The aim of this paper is to study the intestinal absorption and absorption interaction of telmisartan and pitavastatin calcium. An HPLC method was developed and validated to determine telmisartan and pitavastatin calcium in intestinal perfusate simultaneously. The in situ single-pass perfusion in rats was utilized to investigate the effects of concentrations, intestinal segment (duodenum, jejunum, ileum and colon) and co-administrated drugs on absorption. The effective permeability coefficient and the absorption rate constant of telmisartan were higher in the duodenum as compared to other intestinal segments. However, the intestinal absorption of pitavastatin calcium was not segmental dependent. The effective permeability coefficient and absorption rate constant have no significant difference among three concentrations of telmisartan, pitavastatin calcium individually and their combination. The results showed that telmisartan and pitavastatin calcium were transported passively, and telmisartan and pitavastatin calcium could be absorbed well in all intestinal segments. The intestinal absorption parameters revealed the absence of any intestinal absorption interaction when co-administered. Lay Summary: Co-administration of telmisartan and pitavastatin calcium can provide a potential therapeutic strategy for the treatment of concurrent hypertension and hypercholesterolemia. We are investigating the intestinal interaction of these two drugs in rats using the developed HPLC method and in situ single-pass perfusion technology. We will calculate some parameters after administrating two types of drugs either separately or together, which help reflect changes regarding intestinal absorption and penetration. Compared with telmisartan and pitavastatin calcium administrated separately, if parameters significantly change after co-administration, it proves the existence of the intestinal interactions. Moreover, the results might contribute to clinic drug monitoring.

A bioequivalence study of two telmisartan 80 mg tablets in healthy Indonesian subjects: an open label, three-way, three-period, partial replicate crossover study

Telmisartan is highly variable drug indicated for treatment of hypertension. This study aimed to compare the bioavailability of two 80 mg telmisartan tablets in healthy Indonesian subjects. A randomized, open-label, single-dose, three-sequence, three-way, reference-formulation-replicated crossover study was conducted under fasting period with two-week washout period. In this study, 31 Indonesian subjects were enrolled and 28 subjects were completed the study. Serial blood samples were collected up to 72 h following drug administration. Plasma concentrations of telmisartan were determined using high-performance liquid chromatography method with fluorescence detector. The pharmacokinetic parameters of AUC0– t , AUC0–∞, and C max were assessed for bioequivalence. Bioequivalence acceptance was based on predefined criteria of 90% confidence interval (CI) of 80.00–125.00% for AUC parameters and reference-scaled-average bioequivalence of 71.73–139.42% for C max. The 90% CI for AUC0– t , AUC0–∞, and C max was 96.11–107.25%, 93.06–104.36%, and 94.23–127.01%, respectively. These results indicated that the two formulations of telmisartan were bioequivalent.

Telmisartan reverses antiretroviral-induced adipocyte toxicity and insulin resistance in vitro.

Background:Antiretroviral therapy in HIV-positive patients leads to insulin resistance which is central to the pathogenesis of various metabolic abnormalities and cardiovascular disease seen in this patient group. We have investigated the dose–response relationship of telmisartan, an antihypertensive, on adipocytes in vitro in order to determine whether it may have metabolic beneficial effects.Methods:Using in vitro chronic toxicity models (3T3-F442A murine and primary human adipocytes), we evaluated the effects of different concentrations of telmisartan on adipocyte differentiation and adipogenic gene expression using lipid accumulation assays and real-time polymerase chain reaction, respectively. Adipokine secretion and expression of insulin signalling mediators were evaluated using enzyme-linked immunosorbent assays.Results:Telmisartan partially reversed the deleterious effects of antiretrovirals on adipocyte lipid accumulation, expression of adipogenic regulators (peroxisome proliferator receptor-gamma and lipin 1), adipokine secretion and expression of the insulin signalling mediator pAktSer473. The metabolic effects of telmisartan followed a non-monotonic response with the maximal effect observed at 5 µM in the primary human adipocyte model.Conclusion:Telmisartan has beneficial metabolic effects in adipocytes in vitro, but its potential to reduce antiretroviral-induced cardiometabolic disease in HIV-infected individuals needs to be evaluated in a well-designed adequately powered clinical trial.

Bioavailability of Two Different Tablet Formulations of Telmisartan of Two Different Strengths (40 mg and 80 mg) in Healthy Male Mexican Volunteers

Telmisartan is a non-peptide angiotensin II receptor antagonist. In Mexico, it is indicated for the treatment of arterial hypertension and for the prevention of morbidity and mortality of patients ≥ 55 years old with high risk of cardiovascular disease. The aim of these two studies was to compare the bioavailability and to determine the bioequivalence of two test formulations containing 40 mg and 80 mg of oral telmisartan. Two separate, singledose, single-blind, randomized, two-period, crossover studies were conducted. For each study a different set of 30 male subjects completed both studies with a 14-day washout period. In both studies, the study formulations were administered after a 10-hour overnight fast. For pharmacokinetic analysis, blood samples were drawn at baseline, 0.25, 0.5, 0.75, 1, 1.33, 1.67, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours after administration. Plasma concentrations of telmisartan were determined using HPLC coupled with a fluorescence detector. The test and reference formulations were considered bioequivalent if the 90% CI for the geometric mean test/reference ratios were within the predetermined ranges of 80% to 125%.for AUC0-t and AUC0-∞; and 75% to 133% for Cmax. In the study with telmisartan 40 mg, the 90% CI were 81.23%; 104.94% for Cmax, 92.61%; 115.41% for AUC0-t, 91.83%; and 115.05% for AUC0-∞. In the study with telmisartan 80 mg the 90% CI were 86.84%; 121.07% for Cmax, 90.51%; 110.38% for AUC0-t, 90.58%; and 110.96% for AUC0-∞. In both studies, a single dose of the test formulation met the regulatory requirements to assume bioequivalence, based on the rate and extent of absorption.

Telmisartan Induces Growth Inhibition, DNA Double-Strand Breaks and Apoptosis in Human Endometrial Cancer Cells

Telmisartan, an angiotensin II receptor type 1 blocker, is often used as an antihypertension drug, and it has also been characterized as a peroxisome proliferator-activated receptor-gamma (PPARγ) ligand. The purpose of this study was to elucidate the antitumor effects of telmisartan on endometrial cancer cells. We treated three endometrial cancer cell lines with various concentrations of telmisartan, and we investigated the effects of the telmisartan on the cell proliferation, apoptosis, and their related measurements in vitro. We also administered telmisartan to nude mice with experimental tumors to determine its in vivo effects and toxicity. All three endometrial cancer cell lines were sensitive to the growth-inhibitory effect of telmisartan. The induction of apoptosis was confirmed in concert with the altered expression of genes and proteins related to the apoptosis. We also observed that DNA double-strand breaks (DSBs) were induced in HHUA (human endometrial cancer) cells by telmisartan treatment. In addition, experiments in nude mice showed that telmisartan significantly inhibited human endometrial tumor growth, without toxic side effects. Our results suggest that telmisartan might be a new therapeutic option for the treatment of endometrial cancers.

Telmisartan increases lipoprotein lipase expression via peroxisome proliferator-activated receptor-alpha in HepG2 cells

In addition to their hypotensive properties, angiotensin receptor blockers (ARBs) have been shown to exert clinical antidyslipidemic effects. The mechanism underlying these ARB lipid metabolic effects remains unclear. Some ARBs, for example, telmisartan, activate peroxisome proliferator-activated activated receptor-gamma (PPAR-gamma). We hypothesized that PPAR-gamma–activating ARBs might exert antidyslipidemic effects via PPAR-alpha. In this study, we assessed the effect of telmisartan on the expression of PPAR-alpha and lipoprotein lipase (LPL). PPAR-alpha expression was detected by reverse-transcription polymerase chain reaction and Western blot in HepG2 hepatocytes as well as differentiated C2C12 myocytes treated with increasing concentrations of telmisartan (0.1–10 μmol/L) for 48 h. Results showed that 1 μmol/L and 10 μmol/L telmisartan significantly increased the expression of PPAR-alpha mRNA and protein in HepG2 cells (p < 0.01). No effect was shown in differentiated C2C12 cells. Similarly, 1 µmol/L and 10 μmol/L telmisartan significantly increased the expression of LPL mRNA and protein in HepG2 cells (p < 0.01), and this increase was significantly (p < 0.01) inhibited by the PPAR-alpha–specific antagonist MK886. These results indicate that certain of the antidyslipidemic effects of telmisartan might be mediated via increased PPAR-alpha–dependent induction of LPL expression.

P.2.d.001 1,2,3,4-Tetrahydroisoquinoline produces antidepressant-like effects in modified rat forced swimming test: comparison with imipramine

Telmisartan is taken up into human hepatocytes by organic anion-transporting polypeptide (OATP/gene SLCO) and is glucuronized by uridine diphosphate-glucuronosyltransferases (UGTs) into the acylglucuronide, and it is then excreted by transporters such as multidrug resistance 1 (MDR1/gene ABCB1), multidrug resistance protein 2 (MRP2/gene ABCC2), or breast cancer resistance protein (BCRP/gene ABCG2). We elucidated the association of UGTs (1A1, 1A6, 1A7, 1A9 and 2B7), SLCOs (1B1, 1B3 and 2B1), ABCB1, ABCC2 and ABCG2 polymorphisms with steady-state telmisartan pharmacokinetics in 12 Japanese renal transplant recipients.Recipients were given 40 mg of telmisartan for at least 6 months. Blood was sampled 1 y after transplantation. Plasma concentrations of telmisartan were measured by HPLC.In subjects with the ABCC2 − 24C/T genotype, the maximum plasma concentration of telmisartan was significantly greater than that in C/C genotype (96.8 vs. 57.4 ng/ml, respectively, P = 0.0094). In ABCC2 − 24C/C, the second peak plasma concentration of telmisartan was observed 13 h after oral administration, but not ABCC2 − 24C/T genotype group. There was no significant difference in the telmisartan pharmacokinetics between genotype groups of other transporters such as SLCO1B3, ABCB1 and ABCG2 or UGTs.ABCC2 genetic polymorphisms appear to strongly influence inter-individual variation of telmisartan pharmacokinetics. MRP2 may be predominantly involved in the telmisartan pharmacokinetics in humans.

Pharmacokinetic and pharmacogenomic profiles of telmisartan after the oral microdose and therapeutic dose

In this study, we evaluated (a) the contribution of SLCO1B3 and UGT1A polymorphisms to the pharmacokinetics of telmisartan in two forms, a microdose (MD) and a therapeutic dose (TD); (b) linkage disequilibrium (LD) between UGT1A1 and UGT1A3; and (c) linearity in the pharmacokinetics of telmisartan between the two forms. Telmisartan was orally administered at MD condition (100 μg), and then at TD condition (80 mg) to 33 healthy volunteers whose genotypes were prescreened by DMET Plus. Plasma concentrations of telmisartan and its glucuronide were measured by LC-MS/MS, and population pharmacokinetic analysis was performed. No obvious effect of SLCO1B3 polymorphisms (334T>G, 699G>A, and rs11045585) on the pharmacokinetics of telmisartan was observed. The strong LD between UGT1A1*6 and UGT1A3*4a, and between UGT1A1*28 and UGT1A3*2a were observed. After both MD and TD administration, the mean area under the curve0-24 (±standard deviation) of telmisartan was significantly lower and higher in individuals with the UGT1A3*2a (TD, 1701±970 ng hr/ml; MD, 978±537 pg hr/ml) and *4a variants (TD, 5340±1168; MD, 3145±1093), respectively, compared with those in individuals with UGT1A3*1/*1 (TD, 2969±1456; MD, 1669±726). These results were quantitatively confirmed by population pharmacokinetic analysis. Nonlinearity of the dose-exposure relationship was observed between the MD and TD. The haplotypes of UGT1A3 significantly influenced pharmacokinetics of telmisartan and a strong LD between UGT1A1 genotype and UGT1A3 haplotype was observed. These findings are potentially of pharmacological and toxicological importance to the development and clinical use of drugs.

Effect of telmisartan, valsartan and candesartan on mycophenolate mofetil pharmacokinetics in Japanese renal transplant recipients

The aim of this study was to elucidate the effect of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activating angiotensin receptor blocker (ARB) telmisartan and the non-PPAR-gamma activating ARB valsartan and candesartan on mycophenolic acid (MPA) pharmacokinetics in renal transplant recipients. Recipients (n = 10 each group) were randomly given either 40 mg of telmisartan, 80 mg of valsartan or 8 mg of candesartan cilexetil for at least 6 months, and no ARB. Blood was sampled a year after transplantation. Dose-adjusted maximum and trough plasma concentration of MPA co-administered with telmisartan were the lowest in all groups. The mean dose-adjusted area under the concentration curve from 0 to 12 h (AUC(0-12)) and AUC(0-6) of MPA co-administered with telmisartan were significantly lower than that without ARB (98 vs. 138 ng x h/mL/mg, P = 0.0353 and 63 vs. 96 ng x h/mL/mg, P = 0.0305). Coadministration of valsartan and candesartan did not alter MPA pharmacokinetics. The AUC ratio of MPA glucuronide (MPAG)/MPA co-administered with telmisartan was higher than that without ARBs, but not significantly (14.2 vs. 9.1). The mean maximum and minimum plasma concentrations of telmisartan (40 mg) after oral administration were 84 and 15 ng/mL, respectively, and that of valsartan (80 mg) 2220 and 441 ng/mL, respectively. Plasma concentrations of candesartan in most transplant patients were not observed 19 h after oral administration of candesartan cilexeil (8 mg). The degree of drug interaction between MPA and telmisartan was significantly greater than that between MPA and valsartan or candesartan. Uridine diphosphate-glucuronosyltransferase (UGT) 1A9 has been identified as a PPAR-gamma target gene. UGT induction by telmisartan might stimulate MPA glucuronidation. A combination of telmisartan and mycophenolate mofetil might require periodic monitoring of MPA.

Angiotensin type 1 receptor blockers telmisartan and irbesartan activate PPARα

Objective To investigate the effect of telmisartan and irbesartan on PPARα transcriptional activity, and to clarify their molecular mechanisms in improving glucose and lipid metabolism. Methods The structural expression vectors, including pCMV-PPARα, pGL3-PPRE and the internal control vector pRL-TK, were transiently eo-transfected into COS-7 cells using SuperFect, the cells were eontinously cultured with various concentrations of telmisartan and irbesartan, and then the PPRE controlled luciferase activity was determined by using a dual-luciferase reporter gene assay system. PPARα mRNA and protein expression levels were detected by RT-PCR and Western blot after 3T3-L1 adipoeytes were treated with various concentrations of telmisartan or irbesartan. Results (1) Both telmisartan and irbesartan stimulated PPARα transcriptional activity in concentration-and time-dependent manners in cultured COS-7 cells with the maximal effect at 60 h, with the results increased by 3.8 and 2.6 folds respectively at the concentration of 100 μmol/L compared with control group (both P<0.01). (2) The PPARγ antagonist GW9662 did not inhibit fenofibrate, telmisartan and irbesartan-stimulated PPARα transcriptional activities. (3) Both telmisartan and irbesartan increased PPARα mRNA and protein expression levels in a dose-dependent manner in 3T3-L1 adipocytes. Conclusion Angiotensin type 1 receptor blockers, telmisartan and irbesartan, can both increase PPARα transcriptional activity, which may contribute to their metabolic effects. Key words: PPARα; Telmisartan; Irbesartan

No effect of MDR1 C3435T polymorphism on oral pharmacokinetics of telmisartan in 19 healthy Chinese male subjects

Considerable interindividual differences in both drug response and pharmacokinetics of telmisartan have been identified. This study was designed to investigate the influence of MDR1 C3435T polymorphism on pharmacokinetics of telmisartan after a single oral dose in healthy Chinese volunteers. A total of 61 unrelated male volunteers were genotyped for MDR1 C3435T polymorphism by using the polymerase chain reaction-restriction fragment length polymorphism method. Six 3435CC homozygotes, eight 3435CT heterozygotes, and five 3435TT homozygotes were randomly selected and received a single oral dose of 40 mg telmisartan. Plasma concentrations of telmisartan were determined by the high performance liquid chromatography-mass spectrometry method up to 48 h after telmisartan administration. Interindividual variation for t(max), C(max), t(1/2), AUC(0-48), AUC(0-infinity), and clearance (CL) for telmisartan was approximately 6-, 33-, 16-, 17-, 20-, and 20-fold, respectively. C(max) (p=0.010), t(1/2) (p=0.029) and CL (p=0.010) of telmisartan were not normally distributed. MDR1 3435TT homozygotes seemed to show increases in C(max), t(max), t(1/2), AUC(0-48), and AUC(0-infinity). However, no significant differences in C(max), t(max), t(1/2), AUC(0-48), AUC(0-infinity), and CL among MDR1 C3435T genotypes were observed. MDR1 C3435T polymorphism does not affect oral pharmacokinetics of telmisartan.

Telmisartan pharmacokinetics in Japanese renal transplant recipients

Background Telmisartan is taken up into human hepatocytes by organic anion-transporting polypeptide (OATP/gene SLCO) and is glucuronized by uridine diphosphate-glucuronosyltransferases (UGTs) into the acylglucuronide, and it is then excreted by transporters such as multidrug resistance 1 (MDR1/gene ABCB1), multidrug resistance protein 2 (MRP2/gene ABCC2), or breast cancer resistance protein (BCRP/gene ABCG2). We elucidated the association of UGTs ( 1A1, 1A6, 1A7, 1A9 and 2B7), SLCOs ( 1B1, 1B3 and 2B1), ABCB1, ABCC2 and ABCG2 polymorphisms with steady-state telmisartan pharmacokinetics in 12 Japanese renal transplant recipients. Methods Recipients were given 40 mg of telmisartan for at least 6 months. Blood was sampled 1 y after transplantation. Plasma concentrations of telmisartan were measured by HPLC. Results In subjects with the ABCC2 − 24C/T genotype, the maximum plasma concentration of telmisartan was significantly greater than that in C/C genotype (96.8 vs. 57.4 ng/ml, respectively, P = 0.0094). In ABCC2 − 24C/C, the second peak plasma concentration of telmisartan was observed 13 h after oral administration, but not ABCC2 − 24C/T genotype group. There was no significant difference in the telmisartan pharmacokinetics between genotype groups of other transporters such as SLCO1B3, ABCB1 and ABCG2 or UGTs. Conclusions ABCC2 genetic polymorphisms appear to strongly influence inter-individual variation of telmisartan pharmacokinetics. MRP2 may be predominantly involved in the telmisartan pharmacokinetics in humans.

Liver-Specific Peroxisome Proliferator–Activated Receptor α Target Gene Regulation by the Angiotensin Type 1 Receptor Blocker Telmisartan

The angiotensin type 1 receptor blocker (ARB) and peroxisome proliferator-activated receptor (PPAR) gamma modulator telmisartan has been recently demonstrated to reduce plasma triglycerides in nondiabetic and diabetic hypertensive patients. The present study investigates the molecular mechanisms of telmisartans hypolipidemic actions, in particular its effect on the PPARalpha pathway. RESEARCH DESIGN AND METHODS; Regulation of PPARalpha target genes by telmisartan was studied by real-time PCR and Western immunoblotting in vitro and in vivo in liver/skeletal muscle of mice with diet-induced obesity. Activation of the PPARalpha ligand binding domain (LBD) was investigated using transactivation assays. Telmisartan significantly induced the PPARalpha target genes carnitine palmitoyl transferase 1A (CPT1A) in human HepG2 cells and acyl-CoA synthetase long-chain family member 1 (ACSL1) in murine AML12 cells in the micromolar range. Telmisartan-induced CPT1A stimulation was markedly reduced after small interfering RNA-mediated knockdown of PPARalpha. Telmisartan consistently activated the PPARalpha-LBD as a partial PPARalpha agonist. Despite high in vitro concentrations required for PPARalpha activation, telmisartan (3 mg x kg(-1) x day(-1)) potently increased ACSL1 and CPT1A expression in liver from diet-induced obese mice associated with a marked decrease of hepatic and serum triglycerides. Muscular CPT1B expression was not affected. Tissue specificity of telmisartan-induced PPARalpha target gene induction may be the result of previously reported high hepatic concentrations of telmisartan. The present study identifies the ARB/PPARgamma modulator telmisartan as a partial PPARalpha agonist. As a result of its particular pharmacokinetic profile, PPARalpha activation by telmisartan seems to be restricted to the liver. Hepatic PPARalpha activation may provide an explanation for telmisartan's antidyslipidemic actions observed in recent clinical trials.

Receptor-independent intracellular radical scavenging activity of an angiotensin II receptor blocker

Angiotensin II plays a crucial role in the induction of oxidative stress and the pathogenesis of cardiovascular and renal diseases, and the beneficial mechanisms of angiotensin II receptor 1 blockers (ARBs) are multifactorial. We investigated the receptor-independent protective role of an ARB using primary-cultured mesangial cells from angiotensin II receptor 1 knockout or wild-type mice and a highly lipophilic ARB, telmisartan. Intracellular reactive oxygen species were estimated using a fluorogenic probe, CM-H2DCFDA. Non-angiotensin II-induced reactive oxygen species production was generated by exposing cells to hydrogen peroxide alone or after treatment with telmisartan. Flow cytometry analysis showed that angiotensin II induced an increase in oxidant production in a dose-dependent manner in wild-type cells, but not in knockout cells. In contrast, hydrogen peroxide induced oxidative stress in both wild-type and knockout cells. Interestingly, telmisartan attenuated the oxidative stress induced by hydrogen peroxide in both cells, suggesting that it acted via a receptor-independent antioxidant effect. Intracellular concentrations of telmisartan were confirmed by high-performance liquid chromatography analysis. Expression of plasminogen activator inhibitor 1, which is stimulated by oxidative stress, was also attenuated by telmisartan in a receptor-independent as well as receptor-dependent manner. Telmisartan did not change expression levels of antioxidative enzymes such as catalase or glutathione peroxidase. Furthermore, the amelioration of oxidative stress by telmisartan did not involve the peroxisome proliferator-activated receptor-gamma pathway. Telmisartan inhibits intracellular oxidative stress, at least in part, in a receptor-independent manner, possibly owing to its lipophilic and antioxidant structure.

Pharmacokinetic-pharmacodynamic modeling of telmisartan using an indirect response model in spontaneously hypertensive rats

To investigate the pharmacokinetic (PK) and the pharmacodynamic (PD) properties of telmisartan in spontaneously hypertensive (SH) rats using an indirect response and effect-compartment link models, and compare two PK-PD models fitting quality. The SH rats received a single oral dose of 2, 4, and 8 mg/kg of telmisartan. The plasma concentrations of telmisartan were determined by the liquid chromatography-mass spectrum method. The mean arterial blood pressure was measured to characterize the pharmacodynamics of telmisartan by tail-cuff manometry. The relationship for the telmisartan concentration-hypotensive effect in the SH rats was characterized using an indirect response model. The PK parameters showed dose proportionality, with a long terminal half-life of 16 h, a clearance of 0.15 Lxkg( -1) xh( -1), and a volume of distribution of 5.36 Lxkg( -1) in the study. For the indirect response PD model, the estimated K(in) were 36.6, 34.1, and 32.8 %.h( -1), K(out) were 36.7, 34.6, and 31.9 h( -1); the IC(50) values were 86.2, 95.8, and 91.1 ngxmL( -1); and the area under the effect curve (AUEC) were 762.8, 1490.5, and 2086.2 mmHg.h at three doses, respectively. For the effect-compartment model, the K(eo) were 29.4, 33.8, and 28.7 h( -1); the IC(50) values were 78.2, 85.7, and 80.9 ngxmL(-1), and the AUEC were 781.5, 1602.8, and 2215.7 mmHg.h at three doses, respectively. According to Akaike's information criterion values, the proposed indirect response model provided a more appropriate and good-fitting PK/PD characterization of telmisartan than the effect-compartment link model in SH rats.