Lack of inhibition of CYP2C8 by saroglitazar magnesium: In vivo assessment using montelukast, rosiglitazone, pioglitazone, repaglinide and paclitaxel as victim drugs in Wistar rats

Giri, Poonam; Delvadia, Prashant; Ladani, Meera K; Prajapati, Namrata; Gupta, Lakshmikant; Patel, N. K.; Joshi, Vipul; Giri, Shyamkumar; Jain, Mukul; Srinivas, Nuggehally R.; Patel, Pankaj

doi:10.1016/j.ejps.2019.01.005

Cited by 6 publications

(4 citation statements)

References 18 publications

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“…In terms of lipid parameters, saroglitazar resulted in a statistically significant reduction in lipid parameters just like the other glitazars [1,2,30]. Additionally, saroglitazar applies its valuable effects on adipose tissue in a rodent model by limiting diet-induced adipose tissue dysfunction, adipocyte hypertrophy, adipocyte cell damage and extracellular matrix deposition in obesity [31] and coadministration of saroglitazar does not cause clinically relevant drugdrug interaction (as per pharmacokinetic data of diverse CYP2C8 substrates) [32].…”

Section: Discussionmentioning

confidence: 90%

Effect of saroglitazar 2 mg and 4 mg on glycemic control, lipid profile and cardiovascular disease risk in patients with type 2 diabetes mellitus: a 56-week, randomized, double blind, phase 3 study (PRESS XII study)

Krishnappa

Patil

Parmar

et al. 2020

Cardiovasc Diabetol

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Background: The potential for PPAR agonists to positively affect risk of cardiovascular disease in patients with type 2 diabetes (T2DM) is of persistent attention. The PRESS XII study primarily aimed to evaluate the efficacy and safety of saroglitazar (2 mg and 4 mg) as compared to pioglitazone 30 mg on glycemic control in patients with type 2 diabetes mellitus. Methods: In this randomized double-blind study, patients with T2DM [glycosylated hemoglobin (HbA1c) ≥ 7.5%] were enrolled from 39 sites in India. Patients received once-daily doses of either saroglitazar or pioglitazone (1:1:1 allocation ratio) for a total of 24 weeks. Patients were continued in a double blind extension period for an additional 32 weeks. Efficacy evaluations of glycemic parameters [HbA1c (Primary endpoint at week 24), FPG and PPG] and other lipid parameters (TG, LDL-C, VLDL-C, HDL-C, TC, Non HDL-C, Apo A1 and Apo B) were conducted at week 12, 24 and 56 and compared to the baseline levels. The efficacy analyses were performed by using paired t-test and ANCOVA model. Results: A total of 1155 patients were enrolled in this study. The baseline characteristics were similar between the three treatment groups. The within group mean (± SD) change in HbA1c (%) from baseline of the saroglitazar (2 mg and 4 mg) and pioglitazone treatment groups at week 24 were: − 1.38 ± 1.99 for saroglitazar 2 mg; − 1.47 ± 1.92 for saroglitazar 4 mg and − 1.41 ± 1.86 for pioglitazone, respectively. Statistically significant reduction from baseline in HbA1c was observed in each treatment group at week 24 with p-value < 0.016. There was a significant reduction in TG, LDL-C, VLDL-C, TC and Non HDL-C with a significant increase in HDL-C from baseline levels (< 0.016). Most of the AE's were 'mild' to 'moderate' in severity and were resolved by the completion of the study.

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Section: Discussionmentioning

confidence: 90%

Effect of saroglitazar 2 mg and 4 mg on glycemic control, lipid profile and cardiovascular disease risk in patients with type 2 diabetes mellitus: a 56-week, randomized, double blind, phase 3 study (PRESS XII study)

Krishnappa

Patil

Parmar

et al. 2020

Cardiovasc Diabetol

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“…Therefore, due to their experimental setup, a direct cardioprotective effect could explain the reduction in infarct size, which is supported by the infarct-size-limiting effect of acute rosiglitazone treatment [24,[27][28][29]. In addition, all experiments with chronic rosiglitazone treatment in rats used high doses, which resulted in peak plasma concentrations [30,31] exceeding those in humans [32][33][34][35][36][37][38][39][40][41]. The average peak plasma concentration of rosiglitazone resulting from single-dose administration of 1 mg/kg in rats is greater than the peak plasma concentration in humans after single-dose administration of 4 or 8 mg doses [42,43].…”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone Does Not Show Major Hidden Cardiotoxicity in Models of Ischemia/Reperfusion but Abolishes Ischemic Preconditioning-Induced Antiarrhythmic Effects in Rats In Vivo

et al. 2022

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Clinical observations are highly inconsistent with the use of the antidiabetic rosiglitazone regarding its associated increased risk of myocardial infarction. This may be due to its hidden cardiotoxic properties that have only become evident during post-marketing studies. Therefore, we aimed to investigate the hidden cardiotoxicity of rosiglitazone in ischemia/reperfusion (I/R) injury models. Rats were treated orally with either 0.8 mg/kg/day rosiglitazone or vehicle for 28 days and subjected to I/R with or without cardioprotective ischemic preconditioning (IPC). Rosiglitazone did not affect mortality, arrhythmia score, or infarct size during I/R. However, rosiglitazone abolished the antiarrhythmic effects of IPC. To investigate the direct effect of rosiglitazone on cardiomyocytes, we utilized adult rat cardiomyocytes (ARCMs), AC16, and differentiated AC16 (diffAC16) human cardiac cell lines. These were subjected to simulated I/R in the presence of rosiglitazone. Rosiglitazone improved cell survival of ARCMs at 0.3 μM. At 0.1 and 0.3 μM, rosiglitazone improved cell survival of AC16s but not that of diffAC16s. This is the first demonstration that chronic administration of rosiglitazone does not result in major hidden cardiotoxic effects in myocardial I/R injury models. However, the inhibition of the antiarrhythmic effects of IPC may have some clinical relevance that needs to be further explored.

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“…The validated probe drugs for this enzyme are paclitaxel, amodiaquine (FDA guidance), repaglinide, montelukast, and pioglitazone. 9 Therefore, any reference to CYP2C8 in the article should be interpreted with caution.…”

Section: Dear Editormentioning

confidence: 99%

Preclinical Evaluation of Safety of Fucoidan Extracts From Undaria pinnatifida and Fucus vesiculosus for Use in Cancer Treatment

2019

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Lack of inhibition of CYP2C8 by saroglitazar magnesium: In vivo assessment using montelukast, rosiglitazone, pioglitazone, repaglinide and paclitaxel as victim drugs in Wistar rats

Cited by 6 publications

References 18 publications

Effect of saroglitazar 2 mg and 4 mg on glycemic control, lipid profile and cardiovascular disease risk in patients with type 2 diabetes mellitus: a 56-week, randomized, double blind, phase 3 study (PRESS XII study)

Effect of saroglitazar 2 mg and 4 mg on glycemic control, lipid profile and cardiovascular disease risk in patients with type 2 diabetes mellitus: a 56-week, randomized, double blind, phase 3 study (PRESS XII study)

Rosiglitazone Does Not Show Major Hidden Cardiotoxicity in Models of Ischemia/Reperfusion but Abolishes Ischemic Preconditioning-Induced Antiarrhythmic Effects in Rats In Vivo

Preclinical Evaluation of Safety of Fucoidan Extracts From Undaria pinnatifida and Fucus vesiculosus for Use in Cancer Treatment

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