The pharmacokinetics of dronedarone in normolipidemic and hyperlipidemic rats

Jardan, Yousef A. Bin; Brocks, Dion R.

doi:10.1002/bdd.2016

Cited by 14 publications

(5 citation statements)

References 24 publications

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“…Hyperlipidemia is accompanied by a consistent increase in low-density lipoprotein that is a key contributor to an increased risk of atherosclerosis, hypertension, and ischemic heart disease [17, 30]. Furthermore, hyperlipidemia was shown to result in alterations in the pharmacokinetic and pharmacodynamics pattern of some drugs [1, 16, 22, 34, 37]. This may be attributed to reduced unbound fraction, enhanced lipoprotein receptor-mediated drug tissue uptake, and/or altered metabolizing enzyme expression [15, 17, 22, 34].…”

Section: Introductionmentioning

confidence: 99%

Hyperlipidemia Alters the Pharmacokinetics of Posaconazole and Vincristine Upon Co-Administration in Rats

et al. 2017

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ObjectivesCo-administration of posaconazole (PSZ) and vincristine (VCR) in the treatment of patients with acute lymphoblastic leukemia increases the neurotoxicity of VCR. Our aim is to study the effect of increased lipoprotein levels on the pharmacokinetics of PSZ and VCR upon co-administration in rats.MethodsRats were assigned to three groups, normolipidemic (NL), intermediate hyperlipidemic (IHL), and extreme hyperlipidemic (HL) groups. All rats were administered PSZ orally followed by VCR intravenously 4 h later. For the pharmacokinetic study, serial plasma samples were collected over 96 h and for tissue distribution study; plasma, lung, and liver tissues were collected over 48 h post oral dosing.ResultsPosaconazole showed higher plasma concentrations than VCR at all time points. Co-administration of VCR with PSZ reduced PSZ weight normalized oral clearance, increased PSZ area under the plasma concentration–time curve (AUC) from time zero to infinity, showed higher PSZ liver concentrations, and increased VCR volume of distribution of the central compartment. Upon increasing the lipoprotein levels, PSZ showed higher plasma availability and delayed tissue distribution, whereas VCR had shown a significant decrease in PSZ AUC0-24h, AUC0-tlast, and AUCo-inf (NL = IHL > HL) and a significant increase in the volume of distribution (NL = IHL < HL). Vincristine has shown higher tissue uptake and concentrations.ConclusionMonitoring cholesterol and triglyceride levels in patients with acute lymphoblastic leukemia is advisable to decrease VCR neurological side effect incidences and delay the activity of both PSZ and VCR.

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Section: Introductionmentioning

confidence: 99%

Hyperlipidemia Alters the Pharmacokinetics of Posaconazole and Vincristine Upon Co-Administration in Rats

et al. 2017

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“…Pharmacokinetics alterations that are commonly produced by hyperlipidemia include decreased drug clearance and volume of distribution. These changes have been observed for several drugs including amiodarone and dronedarone [2,6]. Stereo-selective changes in the clearance and volume of distribution of ketoconazole were also observed in response to experimental hyperlipidemia where an increase in steady state volume of distribution and a decrease in liver uptake were observed for the (-) enantiomer [7].…”

Section: Introductionmentioning

confidence: 84%

Hyperlipidemia: Insights into Mechanisms Involved in Modulation of Drug Pharmacokinetics and Response

Elsherbiny¹

2020

Egyptian Journal of Basic and Clinical Pharmacology

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Hyperlipidemia is associated with disturbances in plasma lipoproteins. These changes were shown to modify the pharmacokinetics of some lipophilic lipoprotein-bound drugs with some of these changes being clinically significant. In this manuscript potential mechanisms that might be involved in hyperlipidemia-induced changes in drug pharmacokinetics such as modulation of p-glycoproteins and liver metabolising enzymes activities and/or expression were investigated. P-glycoprotein gene expression (MDR1A/B) and activity was assessed in porcine (LLC-PK1) and murine (NRK-52E) proximal tubular renal epithelial cells that were maintained in normolipidemic-or hyperlipidemic-serum containing media and was compared to expression levels in serum-deprived cells. Gene expression of low density lipoprotein receptor (LDLr) and MDR1A/B along with cytochrome P450 CYP3A2 and 2C11 were also investigated in hepatocytes from normolipidemic and hyperlipidemic rats using qRT-PCR. Hyperlipidemic serum did not affect MDR1A/B gene expression in LLC-PK1 and NRK-52E cells. However, it significantly reduced p-glycoprotein activity in rifampin-treated and non-treated LLC-PK1 cells. Interestingly, p-glycoprein gene expression was induced in LLC-PK1 and NRK-52E cell lines upon serum starvation. Moreover, hepatocytes from hyperlipidemic rat livers had reduced LDLr, MDR1A/B, and CYP2C11 mRNA levels compared to normolipidemic rats. It is concluded that hyperlipidemiainduced changes in drug pharmacokinetics might be attributed to modulation of drug efflux/uptake, metabolism and/or excretion. Further, p-glycoprotein gene expression is potentially inducible by serum starvation in renal proximal tubular cells, which might be a novel detoxification mechanism by which these cells adapt to stressful conditions.

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“…Dronedarone (DRN) is a structural analog of amiodarone with a log octanol/water partition coefficient (LogP) of 6.46 [1,2]. It is prescribed to patients with paroxysmal or persistent atrial fibrillation as an antiarrhythmic drug that works to restore the normal sinus rhythm.…”

Section: Introductionmentioning

confidence: 99%

Utilizing Drug Amorphous Solid Dispersions for the Preparation of Dronedarone per os Formulations

Kapourani,

Manioudaki,

Kontogiannopoulos

et al. 2023

Polymers

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Dronedarone (DRN), an antiarrhythmic drug, exhibits potent pharmacological effects in the management of cardiac arrhythmias. Despite its therapeutic potential, DRN faces formulation challenges due to its low aqueous solubility. Hence, the present study is dedicated to the examination of amorphous solid dispersions (ASDs) as a strategic approach for enhancing the solubility of DRN. Initially, the glass forming ability (GFA) of API was assessed alongside its thermal degradation profile, and it was revealed that DRN is a stable glass former (GFA III compound) that remains thermally stable up to approximately 200 °C. Subsequently, five commonly used ASD matrix/carriers, i.e., hydroxypropyl methylcellulose (HPMC), povidone (PVP), copovidone (PVP/VA), Soluplus® (SOL), and Eudragit® E PO (EPO), were screened for the formation of a DRN-based ASD using film casting and solvent shift methods, along with miscibility evaluation measurements. SOL proved to be the most promising matrix/carrier among the others, and, hence, was used to prepare DRN ASDs via the melt-quench method. The physicochemical characterization of the prepared systems (via pXRD) revealed the complete amorphization of the API within the matrix/carrier, while the system was physically stable for at least three months after its preparation. In vitro release studies for the ASDs, conducted under non-sink conditions, revealed the sustained supersaturation of the drug for at least 8 h. Finally, the use of attenuated total reflectance (ATR) FTIR spectroscopy showed the formation of a strong molecular interaction between the drug molecules and SOL.

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The pharmacokinetics of dronedarone in normolipidemic and hyperlipidemic rats

Cited by 14 publications

References 24 publications

Hyperlipidemia Alters the Pharmacokinetics of Posaconazole and Vincristine Upon Co-Administration in Rats

Hyperlipidemia Alters the Pharmacokinetics of Posaconazole and Vincristine Upon Co-Administration in Rats

Hyperlipidemia: Insights into Mechanisms Involved in Modulation of Drug Pharmacokinetics and Response

Utilizing Drug Amorphous Solid Dispersions for the Preparation of Dronedarone per os Formulations

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