The effect of hyperlipidemia on the pharmacokinetics, hepatic and pulmonary uptake of posaconazole in rat

Khalil, Hadeel A.; Elnaggar, Mai M.; Belal, Tarek S.; El-Yazbi, Ahmed F.; Hamdy, Dalia A.

doi:10.1016/j.ejps.2016.05.009

Cited by 13 publications

(32 citation statements)

References 30 publications

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“…Posaconazole is highly protein bound (97–99%) and demonstrates low clearance values between 0.103 and 0.207 L/h/kg. Enterohepatic recirculation was also reported with the use of PSZ, showing a second peak in rats and mice; however, this was not the case in dogs [22, 32]. …”

Section: Introductionmentioning

confidence: 98%

“…Triazole antifungals including fluconazole, voriconazole, itraconazole, and posaconazole (PSZ) are among the common measures taken for the prophylaxis and treatment of invasive fungal infections [18, 40]. Posaconazole is widely used as prophylactic therapy in hematopoietic stem cell transplant recipients with graft-vs.-host disease, or in individuals with hematological malignancies experiencing prolonged neutropenia as a result of intensive chemotherapy [3, 18, 22]. …”

Section: Introductionmentioning

confidence: 99%

“…Posaconazole has a large V d (1774 L), and is considerably bound to plasma proteins with a proportion of 98% to albumin [18, 22, 25]. Posaconazole has a median t 1/2 between 15 and 35 h [7].…”

Section: Introductionmentioning

confidence: 99%

“…As a CYP3A4 inhibitor, PSZ has higher potential for drug–drug interactions with CYP3A4 substrates [18, 23, 25]. In rats, PSZ also follows linear pharmacokinetics, its absorption is slow with the maximum plasma concentration reached within 3–12 h in fed rats and an oral bioavailability of 6.7% [22]. Posaconazole is highly protein bound (97–99%) and demonstrates low clearance values between 0.103 and 0.207 L/h/kg.…”

Section: Introductionmentioning

confidence: 99%

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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: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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“…While much has been discussed concerning DHI in the hyperlipidemia model, the research of the effective ingredients of PAL and HSYA in hyperlipidemia model, nevertheless, has been missed out. The transport of pharmaceutical components is varied due to the interaction between the components [12]. Thus, it is necessary to further study and quantitatively express the interaction and change process of chemical composition in vivo [13,14].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Study on Protocatechuic Aldehyde and Hydroxysafflor Yellow A of Danhong Injection in Rats with Hyperlipidemia

Zhou¹,

Li²,

Jin³

et al. 2018

Pharmacology

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Background: Protocatechuic aldehyde (PAL) and hydroxysafflor yellow A (HSYA) are 2 effective ingredients of Danhong Injection, which is extensively used for the clinical treatment of cardio-cerebrovascular diseases. This study aims to investigate the pharmacokinetic differences between single and combined medication of PAL and HSYA and analyze the interaction of the above effective components in hyperlipidemia rats. Methods: Thirty male SD rats were randomly divided into the control group (n = 6) and the model group (n = 24). The hyperlipidemia model was established by feeding with superfatted forage. The successful model rats were then randomly divided into the PAL group (16 mg/kg), the HSYA group (10 mg/kg), and the combination group (16 mg/kg + 10 mg/kg). Administration through tail-vein, and orbital blood was sampled at different time points. The mass concentration of PAL and HSYA was determined by high performance liquid chromatography (HPLC-DAD). Analysis of pharmacokinetic parameters was conducted by using DAS 3.2.6 software and SPSS 19.0 statistical analysis software. Results: According to the parameters of statistical moment of non-compartmental model, there was a significant difference in plasma clearance (CL) between the PAL group and the drug combination group (p < 0.01), as well as in the area under the first moment of the plasma concentration-time curve and the elimination half-life (t_1/2) between the HSYA group and the drug combination group (p < 0.01) but no obvious differences about the blood concentration time curve area, the average dwell time (MRT), and the peak concentration (C_max; p > 0.05). Conclusion: The combined medication of PAL and HSYA could increase the plasma CL significantly and have a great influence on the absorption of HSYA in rats with hyperlipidemia.

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Slow Metabolism–Driven Amplification of Hepatic PPARγ Agonism Mediates Benzbromarone‐Induced Obesity‐Specific Liver Injury

Li,

Hu,

Zhao

et al. 2024

Advanced Science

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Obesity and nonalcoholic fatty liver disease (NAFLD) are established risk factors for drug‐induced liver injury (DILI). The previous study demonstrates that benzbromarone (BBR), a commonly prescribed pharmaceutical agent for managing gout and hyperuricemia, exacerbates hepatic steatosis and liver injury specifically in obese individuals. However, the precise mechanism underpinning this adverse effect remains incompletely elucidated. Given the significance of BBR and its analogs in anti‐gout/hyperuricemia drug discovery, elucidating the mechanism by which BBR exacerbates obesity‐specific DILI warrants further investigation. In this study, through a combined multi‐omics, pharmacological, and pharmacokinetic approaches, it is found that BBR‐induced obesity‐specific DILI is primarily through the potentiation of peroxisome proliferator‐activated receptor gamma (PPARγ) signaling pathways. Further in vivo and in vitro pharmacokinetic analyses reveal that obese db/db mice exhibited a diminished capacity to metabolize BBR in their livers. This reduction leads to prolonged retention of BBR, subsequently resulting in chronic and sustained hepatic PPARγ agonism. This study demonstrates that a slow metabolism‐driven amplification of hepatic PPARγ agonism mediates BBR‐induced obesity‐specific hepatic steatosis and subsequent DILI, which also emphasizes the importance of the reduced hepatic drug metabolism capacity in patients with obesity or pre‐existing NAFLD in both clinical practice and drug discovery processes.

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The effect of hyperlipidemia on the pharmacokinetics, hepatic and pulmonary uptake of posaconazole in rat

Cited by 13 publications

References 30 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

Pharmacokinetic Study on Protocatechuic Aldehyde and Hydroxysafflor Yellow A of Danhong Injection in Rats with Hyperlipidemia

Slow Metabolism–Driven Amplification of Hepatic PPARγ Agonism Mediates Benzbromarone‐Induced Obesity‐Specific Liver Injury

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