Another string to your bow: machine learning prediction of the pharmacokinetic properties of small molecules

Bassani, Davide; Parrott, Neil John; Manevski, Nenad; Zhang, Jitao David

doi:10.1080/17460441.2024.2348157

Expert Opinion on Drug Discovery

2024

DOI: 10.1080/17460441.2024.2348157

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Another string to your bow: machine learning prediction of the pharmacokinetic properties of small molecules

Davide Bassani,

Neil John Parrott,

Nenad Manevski

et al.

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2024

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Cited by 3 publications

References 134 publications

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Evaluation of Anti-Inflammatory Activity of the New Cardiotonic Steroid γ-Benzylidene Digoxin 8 (BD-8) in Mice

Ferreira,

Medeiros,

Soares

et al. 2024

Cells

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Cardiotonic steroids are known to bind to Na+/K+-ATPase and regulate several biological processes, including the immune response. The synthetic cardiotonic steroid γ-Benzylidene Digoxin 8 (BD-8) is emerging as a promising immunomodulatory molecule, although it has remained largely unexplored. Therefore, we tested the immunomodulatory potential of BD-8 both in vitro and in vivo. Hence, primary mouse macrophages were incubated with combinations of BD-8 and the pro-inflammatory fungal protein zymosan (ZYM). Nitric oxide (NO) production was determined by Griess reagent and cytokines production was assessed by enzyme-linked immunosorbent assay. Inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS), p-nuclear factor kappa B p65 (NF-κB p65), p-extracellular signal-regulated kinase (p-ERK), and p-p38 were evaluated by flow cytometry. Macrophages exposed to BD-8 displayed reduced phagocytic activity, NO levels, and production of the proinflammatory cytokine IL-1β induced by ZYM. Furthermore, BD-8 diminished the expression of iNOS and phosphorylation of NF-κB p65, ERK, and p38. Additionally, BD-8 exhibited anti-inflammatory capacity in vivo in a carrageenan-induced mouse paw edema model. Taken together, these findings demonstrate the anti-inflammatory activity of BD-8 and further reinforce the potential of cardiotonic steroids and their derivatives as immunomodulatory molecules.

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Evaluation of Anti-Inflammatory Activity of the New Cardiotonic Steroid γ-Benzylidene Digoxin 8 (BD-8) in Mice

Ferreira,

Medeiros,

Soares

et al. 2024

Cells

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A Comprehensive Physiologically Based Pharmacokinetic Model for Predicting Vildagliptin Pharmacokinetics: Insights into Dosing in Renal Impairment

Pasha,

Zamir,

Rasool

et al. 2024

Pharmaceuticals

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Physiologically based pharmacokinetic (PBPK) modeling is of great importance in the field of medicine. This study aims to construct a PBPK model, which can provide reliable drug pharmacokinetic (PK) predictions in both healthy and chronic kidney disease (CKD) subjects. To do so, firstly a review of the literature was thoroughly conducted and the PK information of vildagliptin was collected. PBPK modeling software, PK-Sim®, was then used to build and assess the IV, oral, and drug-specific models. Next, the average fold error, visual predictive checks, and predicted/observed ratios were used for the assessment of the robustness of the model for all the essential PK parameters. This evaluation demonstrated that all PK parameters were within an acceptable limit of error, i.e., 2 fold. Also to display the influence of CKD on the total and unbound AUC (the area under the plasma concentration–time curve) and to make modifications in dose, the analysis results of the model on this aspect were further examined. This PBPK model has successfully depicted the variations of PK of vildagliptin in healthy subjects and patients with CKD, which can be useful for medical practitioners in dosage optimization in renal disease patients.

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Pharmacokinetic Study of Oral Disulfiram Suspension and Topical Transdermal Nano-Invasomes Gel in Wistar Rats

Al-Zheery,

Kassab

2024

Al-Rafidain J Med Sci

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Background: Disulfiram (DSF), an FDA-approved pharmaceutical for the management of alcoholism, has demonstrated its efficacy against several kinds of cancer. DSF has limited solubility, a fast metabolism, a short duration of action, and instability in physiological environments, mostly caused by rapid degradation in the acidic gastric environment. Objective: A transdermal gel containing disulfiram, which was loaded into invasomes, was developed to improve the stability of DSF and enable its effective distribution to tumor tissues. Methods: This study included 72 Wistar rats weighing 200±35 g, which were separated into two groups, each of which included 12 animals. Rats were orally provided a dose of 5 mg of pure DSF suspension via oral gavage, and DSF nano-invasomal transdermal gel was then applied to their skin. DSF is determined in rats' plasma by reverse-phase high-performance liquid chromatography (RP-HPLC). Results: The results showed that the maximum effect (Cmax, Tmax, and AUC0-72) were (Cmax=57.3±0.2, Tmax=3.6±0.01 and 562±3. 3ng.h/ml) for oral and (Cmax=138±0.4, Tmax=5.5±0.01 and 2819±6.6 ng. h/ml) for transdermal routes, respectively. Results showed that the time and concentration needed to achieve the maximum effect (Cmax and Tmax) were significantly different between DSF-oral suspension and transdermal invasomal gel (p<0.05). The relative bioavailability for the transdermal route was five times that of the oral route after a single dose administered for 72 hours. Conclusions: The nano-invasomal transdermal gel filled with DSF demonstrated a more convenient way of administering DSF compared to the oral route.

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Another string to your bow: machine learning prediction of the pharmacokinetic properties of small molecules

Cited by 3 publications

References 134 publications

Evaluation of Anti-Inflammatory Activity of the New Cardiotonic Steroid γ-Benzylidene Digoxin 8 (BD-8) in Mice

Evaluation of Anti-Inflammatory Activity of the New Cardiotonic Steroid γ-Benzylidene Digoxin 8 (BD-8) in Mice

A Comprehensive Physiologically Based Pharmacokinetic Model for Predicting Vildagliptin Pharmacokinetics: Insights into Dosing in Renal Impairment

Pharmacokinetic Study of Oral Disulfiram Suspension and Topical Transdermal Nano-Invasomes Gel in Wistar Rats

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