Altered pharmacokinetics and pharmacodynamics of repaglinide by ritonavir in rats with healthy, diabetic and impaired hepatic function

Goud, Thirumaleswara; Maddi, Srinivas; Devanna, N.; Thatipamula, Rajendra Prasad

doi:10.1515/dmpt-2015-0046

Cited by 6 publications

(3 citation statements)

References 22 publications

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“…17 However, disparities exist in the PK and PD parameters of antibacterial drugs between normal and infected animal models. 18 The PK-PD parameters of LVFX in combination with QGYD in infected models hold greater significance and clinical relevance compared to those in normal models. Therefore, we established a pneumonia model induced by MDR PA in rats and further investigated the PK-PD of LVFX alone or in combination with QGYD, providing a robust foundation for the combined use of Chinese and Western medicines in the treatment of MDR PA infections.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Qiguiyin Decoction Sensitizing Levofloxacin Against Multidrug-Resistant Pseudomonas aeruginosa Infection Based on PK-PD and Antibody Chip Technology

Li,

Ji,

Liu

et al. 2024

IDR

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Background: Qiguiyin decoction (QGYD) is a traditional Chinese medicine (TCM) and its combined application with levofloxacin (LVFX) has been confirmed effective in the clinical treatment of multidrug-resistant Pseudomonas aeruginosa (MDR PA) infection. This study investigated the therapeutic effect and possible mechanism of QGYD in sensitizing LVFX against MDR PA infection. Materials and Methods: Pulmonary infections were induced in rats by MDR PA. The changes in pharmacokineticspharmacodynamics (PK-PD) parameters of LVFX after combined with QGYD were investigated in MDR PA-induced rats. Subsequently, the correlation between PK and PD was analyzed and PK-PD models were established to elucidate the relationship between QGYD-induced alterations in LVFX metabolism and its sensitization to LVFX. Antibody chip technology was used to detect the levels of inflammatory factors, suggesting the relationship between the beneficial effect of immune regulation and the sensitization of QGYD. Results: QGYD significantly enhanced the therapeutic efficacy of LVFX against MDR PA infection. The combination of QGYD changed the PK parameters of LVFX such as T max , t 1/2 , MRT, V d /F, CL/F and PD parameters such as MIC, AUC 0-24h /MIC. Predicted results from PK-PD models demonstrated that the antibacterial effect of LVFX was significantly enhanced with the combination of QGYD, consistent with experimental findings. Antibody chip results revealed that the combination of QGYD made IL-1 β, IL-6, TNFα, IL-10, and MCP-1 levels more akin to those of the blank group. Conclusion: These findings indicated that QGYD could change the PK-PD behaviors of LVFX and help the body restore immune balance faster. This implied that a potential drug interaction might occur between QGYD and LVFX, leading to improved clinical efficacy when combined.

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Section: Discussionmentioning

confidence: 99%

Mechanism of Qiguiyin Decoction Sensitizing Levofloxacin Against Multidrug-Resistant Pseudomonas aeruginosa Infection Based on PK-PD and Antibody Chip Technology

Li,

Ji,

Liu

et al. 2024

IDR

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“…Regarding the drug dose and treatment regimen, we mimicked a former study performed on insulin-resistant/type 2 diabetic rats, where repaglinide 0.5 mg/kg/day was administered for 2 weeks . Additionally, this dose was previously used experimentally in a pharmacokinetics and pharmacodynamics study performed on rats with normal, diabetic, and impaired hepatic function, while higher doses of repaglinide 1 and 2 mg/kg were tested for cardioprotective efficacy in an atherosclerotic rat model …”

Section: Methodsmentioning

confidence: 99%

Repaglinide Elicits a Neuroprotective Effect in Rotenone-Induced Parkinson’s Disease in Rats: Emphasis on Targeting the DREAM-ER Stress BiP/ATF6/CHOP Trajectory and Activation of Mitophagy

Motawi

Al-Kady

Senousy

et al. 2022

ACS Chem. Neurosci.

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Repaglinide, a meglitinide insulinotropic antidiabetic, was unraveled as a promising therapeutic agent for Huntington's disease by targeting the neuronal calcium sensor downstream regulatory element antagonist modulator (DREAM). However, its mechanistic profile in Parkinson's disease (PD) especially its impact on endoplasmic reticulum (ER) stress, mitophagy, and their interconnections is poorly elucidated. This study is the first to examine the neuroprotective potential of repaglinide in rotenone-induced PD in rats by exploring its effects on DREAM, BiP/ATF6/CHOP ER stress pathway, apoptosis, mitophagy/ autophagy, oxidative stress, astrogliosis/microgliosis, and neuroinflammation. Male Wistar rats were randomly assigned to four groups: groups 1 and 2 received the vehicle or repaglinide (0.5 mg/kg/day p.o). Groups 3 and 4 received rotenone (1.5 mg/kg/48 h s.c) for 21 days; meanwhile, group 4 additionally received repaglinide (0.5 mg/kg/day p.o) for 15 days starting from day 11. Interestingly, repaglinide lessened striatal ER stress and apoptosis as evidenced by reduced BiP/ATF6/CHOP and caspase-3 levels; however, it augmented striatal DREAM mRNA expression. Repaglinide triggered the expression of the mitophagy marker PINK1 and the autophagy protein beclin1 and alleviated striatal oxidative stress through escalating catalase activity. In addition, repaglinide halted astrocyte/microglial activation and neuroinflammation in the striatum as expressed by reducing glial fibrillary acidic protein (GFAP) and ionized calciumbinding adaptor protein 1 (Iba1) immunostaining and decreasing interleukin (IL)-6 and IL-1β levels. Repaglinide restored striatum morphological alterations, intact neuron count, and neurobehavioral motor performance in rats examined by an open field, grip strength, and footprint gait analysis. Conclusively, repaglinide modulates the DREAM-ER stress BiP/ATF6/CHOP cascade, increases mitophagy/autophagy, inhibits apoptosis, and lessens oxidative stress, astrocyte/microglial activation, and neuroinflammation in PD.

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“…Several studies have reported that ritonavir is a potent inhibitor of CYP3A4 (Kirby et al, 2011). The CYP3A inhibitory activity of ritonavir in rats has been reported with repaglinide, which is primarily metabolised by CYP3A4 in humans (Goud et al, 2016). Particularly pertinent to the current work, a pharmacokinetic interaction between the antimalarial quinine and ritonavir following concurrent administration has been reported, with a marked elevation in the plasma levels of quinine and a pronounced decrease in plasma concentrations of the major metabolite 3hydroxyquinine, which is primarily produced from quinine by CYP3A4 (Soyinka et al, 2010).…”

Section: Atovaquone-proguanil (Ap)mentioning

confidence: 99%

Effect of ritonavir on pharmacokinetics of antimalarial drug combinations in rats

Sunitha

Gudi³

2019

ijrps

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The current treatment for Human Immunodeficiency Virus (HIV) patients coinfected with malaria involves the coadministration of antimalarial and antiretroviral (ARV) drugs. The World Health Organization (WHO) recommends artemisinin-based therapy for malaria that usually consists of artemether, artesunate or dihydroartemisinin with non-artemisinin derivatives such as amodiaquine, lumefantrine and mefloquine. Protease inhibitors (PI) such as ritonavir contribute to the improved health of HIV-positive individuals, and the inclusion of ritonavir in antiretroviral regimens is common in clinical practice. Ritonavir is a potent inhibitor of human CYP3A4, which is the primary enzyme involved in the metabolism of many of artemisinin-based drugs, as well as amodiaquine and proguanil. Upon co-administration, ritonavir can potentially influence the metabolism and thus increase the systemic exposure of these drugs. In order to understand this pharmacokinetic (PK) drug interaction, the current work evaluated the effect of ritonavir (50 mg/kg orally) on the PK of antimalarial drug combinations in Sprague Dawley (SD) rats. When co-administered with ritonavir, the exposure (AUC) of the antimalarial drugs artemether, artesunate and proguanil was increased by approximately 3.5-fold. Correspondingly, peak plasma concentrations (Cmax) of these drugs increased as well. There was no apparent influence of ritonavir on the PK of lumefantrine, amodiaquine and atovaquone. This study demonstrates the potential influence of ritonavir on the pharmacokinetics of at least some anti-malarial drugs, likely a result of inhibition of CYP3A. Further evaluation of clinically relevant drug interaction in humans may be warranted to ensure safe and effective use of anti-malarial and anti-HIV drugs concomitantly.

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Altered pharmacokinetics and pharmacodynamics of repaglinide by ritonavir in rats with healthy, diabetic and impaired hepatic function

Abstract: The significant difference in the PK/PD changes have been due to the increased plasma exposure and decreased total body clearance of repaglinide, which may be due to the inhibition of the CYP P450 metabolic system and organic anion-transporting polypeptide transporter by ritonavir.

Cited by 6 publications

References 22 publications

Mechanism of Qiguiyin Decoction Sensitizing Levofloxacin Against Multidrug-Resistant Pseudomonas aeruginosa Infection Based on PK-PD and Antibody Chip Technology

Mechanism of Qiguiyin Decoction Sensitizing Levofloxacin Against Multidrug-Resistant Pseudomonas aeruginosa Infection Based on PK-PD and Antibody Chip Technology

Repaglinide Elicits a Neuroprotective Effect in Rotenone-Induced Parkinson’s Disease in Rats: Emphasis on Targeting the DREAM-ER Stress BiP/ATF6/CHOP Trajectory and Activation of Mitophagy

Effect of ritonavir on pharmacokinetics of antimalarial drug combinations in rats

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