Effect of multidose cilostazol on pharmacokinetic and lipid profile of atorvastatin in male Wistar rats

Vats, Rahul; Varanasi, Kanthikiran V S; Arla, Rambabu; Veeraraghavan, Sridhar; Rajak, Shraddha; Murthy, Aditya

doi:10.1111/j.2042-7158.2012.01542.x

Cited by 5 publications

(5 citation statements)

References 31 publications

(41 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The drug is a CYP3A4 substrate, and most of CYP3A4 substrates are P-gp substrates as well (Boyd et al, 2000). Vatsa et al stated that atorvastatin is a P-gp substrate at lower dose and an inhibitor at higher doses (Vatsa et al, 2012). The P-gp substrate activity of atorvastatin was also suggested by some other studies (Williams and Feely, 2002;Wu et al, 2000).…”

Section: Discussionmentioning

confidence: 73%

“…Vatsa et al reported that atorvastatin is a moderate substrate for CYP P450 and is extensively metabolized via CYP P450-mediated oxidation and phase II glucuronidation both in humans and rats (Vatsa et al, 2012). The drug is a CYP3A4 substrate, and most of CYP3A4 substrates are P-gp substrates as well (Boyd et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…It reduces total cholesterol, LDL, and triglyceride (TG) while elevating the blood level of high -density lipoprotein (HDL). It shows poor oral bioavaila -bility (12% in humans and 6% in rats), poor solubility, and extensive hepatic first-pass biotransformation, preventing its effectiveness in most chemotherapeutic applications (Adams et al, 2012;Horwich and McLellan, 2007;Rodde et al, 2014;Vatsa et al, 2012).…”

mentioning

confidence: 99%

See 2 more Smart Citations

In vitro and in situ effects of atorvastatin and ezetimibe on P-glycoprotein expression and function

Abbasi¹,

Valizadeh²,

Hamishehkar³

et al. 2016

Bangladesh J Pharmacol

View full text Add to dashboard Cite

P-glycoprotein (P-gp) is a membrane transporter responsible for the active efflux from the cell. Inhibition of the activity may lead to clinically significant drug-drug interactions. This study was performed to investigate the effects of atorvastatin and ezetimibe on the function and expression of P-gp. The in vitro rhodamine-123 (Rho123) efflux assay and Western blot in Caco-2 cells, and the in situ rat single-pass intestinal permeability model followed by high performance liquid chromatography were developed. Rho123 intracellular accumulation in 100 µM of atorvastatin- and ezetimibe-treated cells was significantly higher than that in control cells (p<0.05). P-gp expression was decreased by 100 µM atorvastatin and ezetimibe. Intestinal effective permeability of digoxin in the presence of atorvastatin (3 and 100 µM), ezetimibe (10 and 100 µM) was significantly increased (p<0.05). Both drugs inhibited P-gp activity in vitro and in situ. Atorvastatin and ezetimibe down-regulated the expression of P-gp in vitro. Video Clip of Methodology:<a href="https://youtube.com/v/BQuz1ER3_NQ">Single-pass intestinal permeability</a>: 17 min 26 sec

show abstract

Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

In vitro and in situ effects of atorvastatin and ezetimibe on P-glycoprotein expression and function

Abbasi¹,

Valizadeh²,

Hamishehkar³

et al. 2016

Bangladesh J Pharmacol

View full text Add to dashboard Cite

show abstract

“…However, most studies reporting effects of ATV other than reducing cholesterol synthesis in rats have given ATV doses (10 mg/kg) much larger than those prescribed in humans (up to 80 mg/day or <2 mg/kg); in these 10 mg/kg conditions, levels of ATV in rat blood reach 500–1000 nM (Vats et al . ; Kim et al . ), being o‐ATV levels in plasma similar to those of ATV (Crevar‐Sakač et al .…”

Section: Methodsmentioning

confidence: 99%

Specific rescue by ortho‐hydroxy atorvastatin of cortical GABAergic neurons from previous oxygen/glucose deprivation: role of pCREB

Guirao

Martí-Sistac

DeGregorio-Rocasolano

et al. 2017

Journal of Neurochemistry

View full text Add to dashboard Cite

The statin atorvastatin (ATV) given as a post-treatment has been reported beneficial in stroke, although the mechanisms involved are not well understood so far. Here, we investigated in vitro the effect of post-treatment with ATV and its main bioactive metabolite ortho-hydroxy ATV (o-ATV) on neuroprotection after oxygen and glucose deprivation (OGD), and the role of the pro-survival cAMP response element-binding protein (CREB). Post-OGD treatment of primary cultures of rat cortical neurons with o-ATV, but not ATV, provided neuroprotection to a specific subset of cortical neurons that were large and positive for glutamic acid decarboxylase (large-GAD neurons, GABAergic). Significantly, only these GABAergic neurons showed an increase in phosphorylated CREB (pCREB) early after neuronal cultures were treated post-OGD with o-ATV. We found that o-ATV, but not ATV, increased the neuronal uptake of glutamate from the medium; this provides a rationale for the specific effect of o-ATV on pCREB in large-GABAergic neurons, which have a higher ratio of synaptic (pCREB-promoting) vs extrasynaptic (pCREB-reducing) N-methyl-D-aspartate (NMDA) receptors (NMDAR) than that of small-non-GABAergic neurons. When we pharmacologically increased pCREB levels post-OGD in non-GABAergic neurons, through the selective activation of synaptic NMDAR, we observed as well long-lasting neuronal survival. We propose that the statin metabolite o-ATV given post-OGD boosts the intrinsic pro-survival factor pCREB in large-GABAergic cortical neurons in vitro, this contributing to protect them from OGD.

show abstract

“…The drug sacs were then placed in individual incubation chambers containing 20 ml of the oxygenated buffer at 37 °C. The P app values, expressed in cm/s, were calculated using the following equation :

P_{app} = (d Q / d t) / (A . C_{o})

where d Q /d t is the rate of appearance of LPV in the everted gut sac (receiver compartment), C o is the initial concentration of CLZ outside the everted gut sac (donor compartment) and A is the total cross sectional area of tissue.…”

Section: Methodsmentioning

confidence: 99%

Drug–drug interaction study to assess the effects of atorvastatin co‐administration on pharmacokinetics and anti‐thrombotic properties of cilostazol in male Wistar rats

Vats

Varanasi

Arla

et al. 2012

Biopharm & Drug Disp

Self Cite

View full text Add to dashboard Cite

Cilostazol (CLZ) and atorvastatin (ATV) are often co-prescribed to treat conditions such as peripheral arterial disease. In the present study, the drug-drug interaction potential of multi-dose ATV co-administration with CLZ on both pharmacokinetics and the anti-thrombotic property of CLZ is demonstrated. The pharmacokinetic parameters of CLZ (6 mg/kg, twice daily) were determined in male Wistar rats after 7 days co-administration with ATV (5 mg/kg, once daily) in order to assess the interaction potential between CLZ and ATV on chronic treatment. In vitro metabolic inhibition and everted gut sac studies were conducted to elucidate the mechanism of this interaction. Pharmacodynamic drug-drug interaction was evaluated on anti-thrombotic models including time to occlusion, platelet aggregation and rat tail bleeding time. A validated LC-MS/MS method was employed simultaneously to quantify both ATV and CLZ in rat plasma matrix. A statistically significant increase in systemic exposure (Css(max) by ~1.75 fold; AUC by ~3.0 fold) to CLZ was observed in ATV pre-treated rats. In vitro metabolism studies using liver microsomes (RLM and HLM) demonstrated statistically significant inhibition of CLZ metabolism when co-incubated with ATV. No change in apparent permeability of CLZ was observed in the presence of ATV. Atorvastatin showed a significant delay in artery occlusion time without altering CLZ's bleeding time and platelet aggregation profile. Collectively the results of these studies provide metabolic insight into the nature of drug-drug interaction between the selected drugs. Co-administration with ATV influences the pharmacokinetics and anti-thrombotic property of CLZ. A thorough clinical investigation is required before extrapolation of data to humans.

show abstract

Effect of multidose cilostazol on pharmacokinetic and lipid profile of atorvastatin in male Wistar rats

Abstract: Multi-dose administration of CLZ influences the pharmacokinetics and lipid-lowering properties of ATV. Collectively, an apparent interaction between selected drugs was evident.

Cited by 5 publications

References 31 publications

<i>In vitro</i> and <i>in situ</i> effects of atorvastatin and ezetimibe on P-glycoprotein expression and function

<i>In vitro</i> and <i>in situ</i> effects of atorvastatin and ezetimibe on P-glycoprotein expression and function

Specific rescue by ortho‐hydroxy atorvastatin of cortical GABAergic neurons from previous oxygen/glucose deprivation: role of pCREB

Drug–drug interaction study to assess the effects of atorvastatin co‐administration on pharmacokinetics and anti‐thrombotic properties of cilostazol in male Wistar rats

Contact Info

Product

Resources

About