A comparison of in vitro ADME properties and pharmacokinetics of azithromycin and selected 15-membered ring macrolides in rodents

Milić, Astrid; Mihaljević, Vlatka Bencetić; Ralić, Jovica; Bokulić, Ana; Nožinić, Danijela; Tavčar, Branka; Mildner, Boris; Munić, Vesna; Malnar, Ivica; Padovan, Jasna

doi:10.1007/s13318-013-0155-8

Cited by 7 publications

(5 citation statements)

References 36 publications

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“…The drugs were administered orally (by oral gavage) for 4 weeks: AZM (at a dose of 50 mg/kg) was administered once daily in the first week of the experiment and then 3 times a week (every second or third day), and LR (at a dose of 3 × 10 8 CFU/kg) was administered once daily throughout the experiment. The AZM dose was calculated [ 80 ] based on its antimicrobial dose used in patients and the antibiotic AZM dose, reported to affect the rat skeletal system [ 49 ], taking into consideration its bioavailability in rats [ 81 ]. The dose of the probiotic was chosen based on previous studies [ 82 , 83 ].…”

Section: Methodsmentioning

confidence: 99%

Effect of Administration of Azithromycin and/or Probiotic Bacteria on Bones of Estrogen-Deficient Rats

et al. 2022

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The gut microbiota plays an important role in maintaining homeostasis, including that of the skeletal system. Antibiotics may affect the skeletal system directly or indirectly by influencing the microbiota. Probiotic bacteria have been reported to favorably affect bones in conditions of estrogen deficiency. The aim of this study was to investigate the effects of azithromycin (AZM) administered alone or with probiotic bacteria (Lactobacillus rhamnosus; LR) on bones in estrogen-deficient rats. The experiments were carried out on mature rats divided into five groups: non-ovariectomized (NOVX) control rats, ovariectomized (OVX) control rats, and OVX rats treated with: LR, AZM, or AZM with LR. The drugs were administered for 4 weeks. Serum biochemical parameters, bone mineralization, histomorphometric parameters, and mechanical properties were examined. Estrogen deficiency increased bone turnover and worsened cancellous bone microarchitecture and mechanical properties. The administration of LR or AZM slightly favorably affected some skeletal parameters of estrogen-deficient rats. The administration of AZM with LR did not lead to the addition of the effects observed for the separate treatments, indicating that the effects could be microbiota-mediated.

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Section: Methodsmentioning

confidence: 99%

Effect of Administration of Azithromycin and/or Probiotic Bacteria on Bones of Estrogen-Deficient Rats

et al. 2022

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“…A compound profile (Table 2) for azithromycin was created based on physiochemical properties and pharmacokinetic parameters [35][36][37][38][39][40][41]. Oral absorption was characterized using the ADAM module, and intrinsic solubility was predicted using the Simcyp ® prediction toolbox.…”

Section: Azithromycin Model Development and Verification In Healthy V...mentioning

confidence: 99%

PBPK Modeling of Azithromycin Systemic Exposure in a Roux-en-Y Gastric Bypass Surgery Patient Population

Avvari,

Cusumano,

Jogiraju

et al. 2023

Pharmaceutics

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In this investigation, PBPK modeling using the Simcyp® Simulator was performed to evaluate whether Roux-en-Y gastric bypass (RYGB) surgery impacts the oral absorption and bioavailability of azithromycin. An RYGB surgery patient population was adapted from the published literature and verified using the same probe medications, atorvastatin and midazolam. Next, a PBPK model of azithromycin was constructed to simulate changes in systemic drug exposure after the administration of different oral formulations (tablet, suspension) to patients pre- and post-RYGB surgery using the developed and verified population model. Clinically observed changes in azithromycin systemic exposure post-surgery following oral administration (single-dose tablet formulation) were captured using PBPK modeling based on the comparison of model-predicted exposure metrics (Cmax, AUC) to published clinical data. Model simulations predicted a 30% reduction in steady-state AUC after surgery for three- and five-day multiple dose regimens of an azithromycin tablet formulation. The relative bioavailability of a suspension formulation was 1.5-fold higher than the tablet formulation after multiple dosing. The changes in systemic exposure observed after surgery were used to evaluate the clinical efficacy of azithromycin against two of the most common pathogens causing community acquired pneumonia based on the corresponding AUC24/MIC pharmacodynamic endpoint. The results suggest lower bioavailability of the tablet formulation post-surgery may impact clinical efficacy. Overall, the research demonstrates the potential of a PBPK modeling approach as a framework to optimize oral drug therapy in patients post-RYGB surgery.

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“…In an additional study with P-gp inhibitor GF120918 (data not shown), this efflux ratio in clone 79 was diminished for erythromycin to unity. Erythromycin has been reported to give false negative identification as a P-gp substrate in MDR1-MDCK and MDCK-WT due to a high efflux ratio in WT cells and has shown poor in vitro permeability across other cell lines (12,32,33).…”

Section: Bi-directional Transport Across Different Cell Linesmentioning

confidence: 99%

Isolation of MDCK cells with low expression of mdr1 gene and their use in membrane permeability screening

et al. 2021

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The Madin-Darby canine kidney (MDCK) cell line is frequently used for permeability screening in drug discovery. It contains endogenous transporters, most prominently canine multidrug resistance P-glycoprotein (Mdr1), which can interfere with studies of P-glycoprotein substrate assessment and permeability measurements. Because MDCK wild type (WT) is genetically heterogeneous, an isolation procedure was investigated in this study to obtain the subclonal line with low P-glycoprotein expression. The best clone obtained had up to 3-fold lower amprenavir efflux and P-glycoprotein expression in comparison to WT. Of 12 standard compounds tested that exhibited active efflux in WT cells, 11 showed a decrease in efflux in the isolated clone. However, the decrease was not below the cut-off value of 2, indicating residual P--glycoprotein activity. Clone isolation via the limiting dilution method, combined with bidirectional amprenavir permeability for clone selection, successfully identified MDCK clones with substantially lower P-glycoprotein efflux and has been demonstrated as a useful tool for assessing passive permeability in early drug discovery.

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A comparison of in vitro ADME properties and pharmacokinetics of azithromycin and selected 15-membered ring macrolides in rodents

Cited by 7 publications

References 36 publications

Effect of Administration of Azithromycin and/or Probiotic Bacteria on Bones of Estrogen-Deficient Rats

Effect of Administration of Azithromycin and/or Probiotic Bacteria on Bones of Estrogen-Deficient Rats

PBPK Modeling of Azithromycin Systemic Exposure in a Roux-en-Y Gastric Bypass Surgery Patient Population

Isolation of MDCK cells with low expression of mdr1 gene and their use in membrane permeability screening

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