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Pharmaceutics
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ADME Properties in the Drug Delivery
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ADME Properties in the Drug Delivery

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: 10 March 2025 | Viewed by 8880

Special Issue Editors

Dr. Luciana Scotti

E-Mail Website
Guest Editor
Laboratório de Tecnologia Farmacêutica, Federal University of Paraíba, Campus I, João Pessoa 58051-970, PB, Brazil
Interests: molecular modeling; cheminformatic; natural products
Special Issues, Collections and Topics in MDPI journals
Dr. Marcus Tullius Scotti

E-Mail Website
Guest Editor
Department of Chemistry, Federal University of Paraíba, João Pessoa, PB, Brazil
Interests: QSAR; medicinal chemistry; natural products; cheminformatic
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent decades, the identification of thousands of lead compounds, through the development of analytical, synthetic, and computational techniques, has occurred. However, the path followed by a bioactive compound to become a drug is long and involves differing methodologies. Different variables must be considered, such as pharmacokinetics, drug interactions, efficacy, and safety, among others. The process is long and expensive. In pharmaceutical studies, pharmacokinetic properties include absorption, distribution, metabolism, and excretion (ADME).

In recent decades, ADME properties have turned out to be the main factors that cause the failure of bioactive compound candidates for new drugs. Yet, during the development of bioassay techniques, biotech methods, bio- guided phytochemical studies, automated high-throughput screening, and high-performance analytical methods have introduced new concepts in drug research. In vitro and/or computational models allow for the study of parameters that influence the pharmacokinetics of possible future drugs. Traditional in vivo studies provide exact pharmacokinetic profiles, including apparent problems in dose variations, but in vitro and in silico work, which is increasingly reported in the literature, provides reliable predictions, saves time and expenses, and avoids ethical complications. Through such studies, the researcher identifies development problems, which include low solubility and hence poor bioavailability of orally administered drug and/or formulation problems. Pharmaceutical industries invest a lot of money in high-throughput in vitro and in vivo ADME screening. Undesirable pharmacokinetic profiles are soon identified, and alternative studies are performed to correct the problem.

Decreasing the time in the process of searching for new drugs increases the investigation of characteristics related to structure such as permeation, distribution, metabolism, and toxicity, including molecular interactions, tissue permeations, metabolic pathway, etc. This issue will report recent ADME properties studies in drug delivery.

Prof. Dr. Luciana Scotti
Dr. Marcus Tullius Scotti
Guest Editor

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug delivery
  • ADMET
  • medicinal chemistry
  • pharmacokinetic properties

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Published Papers (5 papers)

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Research

12 pages, 1659 KiB  
Article
Comparative Pharmacokinetic Assessment of Curcumin in Rats Following Intratracheal Instillation Versus Oral Administration: Concurrent Detection of Curcumin and Its Conjugates in Plasma by LC-MS/MS
by Nan Li, Jinle Lou, Lingchao Wang, Wenpeng Zhang, Chunmei Jin and Xiaomei Zhuang
Pharmaceutics 2024, 16(11), 1459; https://doi.org/10.3390/pharmaceutics16111459 - 15 Nov 2024
Viewed by 535
Abstract
Objective: To establish and validate an LC-MS/MS method for the simultaneous determination of curcumin (CUR) as well as its glucuronide conjugate (COG) and sulfate conjugate (COS) in rat plasma. The method was employed to evaluate and compare the pharmacokinetic behaviors of curcumin following [...] Read more.
Objective: To establish and validate an LC-MS/MS method for the simultaneous determination of curcumin (CUR) as well as its glucuronide conjugate (COG) and sulfate conjugate (COS) in rat plasma. The method was employed to evaluate and compare the pharmacokinetic behaviors of curcumin following oral and intratracheal administration in rats. Methods: Rat plasma samples were separated by chromatography on a C18 column after protein precipitation with acetonitrile. Gradient elution with a mobile phase of 0.5 mM ammonium acetate in acetonitrile was utilized. Mass spectrometry detection incorporated an electrospray ionization (ESI) source, multiple reaction monitoring (MRM), and dual-mode (positive and negative) scanning for quantitative analysis. A total of 12 SD rats were randomly divided into two groups and were orally (20 mg/kg) or intratracheally (10 mg/kg) administrated curcumin, respectively. CUR, COG, and COS concentrations in plasma were measured to assess pharmacokinetic disparities. Results: The method demonstrated linearity within the ranges of 2–400 ng/mL for CUR and COS and 5–1000 ng/mL for COG. Intratracheal administration significantly elevated CUR plasma concentrations compared to oral administration. The exposure of COG was higher than COS following oral administration. Conversely, intratracheal administration resulted in markedly higher COS exposure, with no significant difference in COG exposure after dose normalization between oral and inhalation routes. Conclusions: The established LC-MS/MS method provides a reliable tool for the simultaneous measurement of CUR, COG, and COS in rat plasma, facilitating preclinical pharmacokinetic investigations. The study reveals distinct pharmacokinetic profiles for CUR following oral versus intratracheal administration, suggesting that inhalation may offer superior therapeutic efficacy. Full article
(This article belongs to the Special Issue ADME Properties in the Drug Delivery)
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15 pages, 3278 KiB  
Article
Pharmacometabolomics Approach to Explore Pharmacokinetic Variation and Clinical Characteristics of a Single Dose of Desvenlafaxine in Healthy Volunteers
by Anne Michelli Reis Silveira, Salvador Sánchez-Vinces, Alex Ap. Rosini Silva, Karen Sánchez-Luquez, Pedro Henrique Dias Garcia, Caroline de Moura Garcia, Rhubia Bethania Socorro Lemos de Brito, Ana Lais Vieira, Lucas Miguel de Carvalho, Marcia Ap. Antonio and Patrícia de Oliveira Carvalho
Pharmaceutics 2024, 16(11), 1385; https://doi.org/10.3390/pharmaceutics16111385 - 28 Oct 2024
Viewed by 836
Abstract
This study investigated the effects of a single dose of desvenlafaxine via oral administration on the pharmacokinetic parameters and clinical and laboratory characteristics in healthy volunteers using a pharmacometabolomics approach. In order to optimize desvenlafaxine’s therapeutic use and minimize potential adverse effects, this [...] Read more.
This study investigated the effects of a single dose of desvenlafaxine via oral administration on the pharmacokinetic parameters and clinical and laboratory characteristics in healthy volunteers using a pharmacometabolomics approach. In order to optimize desvenlafaxine’s therapeutic use and minimize potential adverse effects, this knowledge is essential. Methods: Thirty-five healthy volunteers were enrolled after a health trial and received a single dose of desvenlafaxine (Pristiq®, 100 mg). First, liquid chromatography coupled to tandem mass spectrometry was used to determine the main pharmacokinetic parameters. Next, ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry was used to identify plasma metabolites with different relative abundances in the metabolome at pre-dose and when the desvenlafaxine peak plasma concentration was reached (pre-dose vs. post-dose). Results: Correlations were observed between metabolomic profiles, such as tyrosine, sphingosine 1-phosphate, and pharmacokinetic parameters, as well as acetoacetic acid and uridine diphosphate glucose associated with clinical characteristics. Our findings suggest that desvenlafaxine may have a broader effect than previously thought by acting on the proteins responsible for the transport of various molecules at the cellular level, such as the solute carrier SLC and adenosine triphosphate synthase binding cassette ABC transporters. Both of these molecules have been associated with PK parameters and adverse events in our study. Conclusions: This altered transporter activity may be related to the reported side effects of desvenlafaxine, such as changes in blood pressure and liver function. This finding may be part of the explanation as to why people respond differently to the drug. Full article
(This article belongs to the Special Issue ADME Properties in the Drug Delivery)
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19 pages, 6792 KiB  
Article
Computational and ADMET Predictions of Novel Compounds as Dual Inhibitors of BuChE and GSK-3β to Combat Alzheimer’s Disease
by Saurabh G. Londhe, Vinayak Walhekar, Mangala Shenoy, Suvarna G. Kini, Marcus T. Scotti, Luciana Scotti and Dileep Kumar
Pharmaceutics 2024, 16(8), 991; https://doi.org/10.3390/pharmaceutics16080991 - 26 Jul 2024
Viewed by 1482
Abstract
Background: Alzheimer’s disease is a serious and widespread neurodegenerative illness in the modern healthcare scenario. GSK-3β and BuChE are prominent enzymatic targets associated with Alzheimer’s disease. Co-targeting GSK3β and BChE in Alzheimer’s disease helps to modify disease progression and enhance cognitive function by [...] Read more.
Background: Alzheimer’s disease is a serious and widespread neurodegenerative illness in the modern healthcare scenario. GSK-3β and BuChE are prominent enzymatic targets associated with Alzheimer’s disease. Co-targeting GSK3β and BChE in Alzheimer’s disease helps to modify disease progression and enhance cognitive function by addressing both tau pathology and cholinergic deficits. However, the treatment arsenal for Alzheimer’s disease is extremely inadequate, with present medications displaying dismal success in treating this never-ending ailment. To create novel dual inhibitors, we have used molecular docking and dynamics analysis. Our focus was on analogs formed from the fusion of tacrine and amantadine ureido, specifically tailored to target GSK-3β and BuChE. Methods: In the following study, molecular docking was executed by employing AutoDock Vina and molecular dynamics and ADMET predictions were performed using the Desmond and Qikprop modules of Schrödinger. Results: Our findings unveiled that compounds DKS1 and DKS4 exhibited extraordinary molecular interactions within the active domains of GSK-3β and BuChE, respectively. These compounds engaged in highly favorable interactions with critical amino acids, including Lys85, Val135, Asp133, and Asp200, and His438, Ser198, and Thr120, yielding encouraging docking energies of −9.6 and −12.3 kcal/mol. Additionally, through extensive molecular dynamics simulations spanning a 100 ns trajectory, we established the robust stability of ligands DKS1 and DKS4 within the active pockets of GSK-3β and AChE. Particularly noteworthy was DKS5, which exhibited an outstanding human oral absorption rate of 79.792%, transcending the absorption rates observed for other molecules in our study. Conclusion: In summary, our in silico findings have illuminated the potential of our meticulously designed molecules as groundbreaking agents in the fight against Alzheimer’s disease, capable of simultaneously inhibiting both GSK-3β and BuChE. Full article
(This article belongs to the Special Issue ADME Properties in the Drug Delivery)
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16 pages, 1859 KiB  
Article
Pharmacokinetic–Pharmacodynamic Modeling of Midazolam in Pediatric Surgery
by Carmen Flores-Pérez, Luis Alfonso Moreno-Rocha, Juan Luis Chávez-Pacheco, Norma Angélica Noguez-Méndez, Janett Flores-Pérez, Delfina Ortiz-Marmolejo and Lina Andrea Sarmiento-Argüello
Pharmaceutics 2023, 15(11), 2565; https://doi.org/10.3390/pharmaceutics15112565 - 1 Nov 2023
Cited by 1 | Viewed by 2518
Abstract
Midazolam (MDZ) is used for sedation in surgical procedures; its clinical effect is related to its receptor affinity and the dose administered. Therefore, a pharmacokinetic–pharmacodynamic (PK-PD) population model of MDZ in pediatric patients undergoing minor surgery is proposed. A descriptive, observational, prospective, and [...] Read more.
Midazolam (MDZ) is used for sedation in surgical procedures; its clinical effect is related to its receptor affinity and the dose administered. Therefore, a pharmacokinetic–pharmacodynamic (PK-PD) population model of MDZ in pediatric patients undergoing minor surgery is proposed. A descriptive, observational, prospective, and longitudinal, study that included patients of both sexes, aged 2–17 years, ASA I/II, who received MDZ in IV doses (0.05 mg/kg) before surgery. Three blood samples were randomly taken between 5–120 min; both sedation by the Bispectral Index Scale (BIS) and its adverse effects were recorded. The PK-PD relationship was determined using a nonlinear mixed-effects, bicompartmental first-order elimination model using Monolix Suite™. Concentrations and the BIS were fitted to the sigmoid Emax PK-PD population and sigmoid Emax PK/PD indirect binding models, obtaining drug concentrations at the effect site (biophase). The relationship of concentrations and BIS showed a clockwise hysteresis loop, probably indicating time-dependent protein binding. Of note, at half the dose used in pediatric patients, adequate sedation without adverse effects was demonstrated. Further PK-PD studies are needed to optimize dosing schedules and avoid overdosing or possible adverse effects. Full article
(This article belongs to the Special Issue ADME Properties in the Drug Delivery)
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23 pages, 3070 KiB  
Article
Evaluation of Alectinib Metabolic Stability in HLMs Using Fast LC-MS/MS Method: In Silico ADME Profile, P450 Metabolic Lability, and Toxic Alerts Screening
by Mohamed W. Attwa, Haitham AlRabiah, Gamal A. E. Mostafa and Adnan A. Kadi
Pharmaceutics 2023, 15(10), 2449; https://doi.org/10.3390/pharmaceutics15102449 - 11 Oct 2023
Cited by 2 | Viewed by 2247
Abstract
Alectinib, also known as Alecensa®, is prescribed for the therapeutic treatment of individuals diagnosed with metastatic non-small cell lung cancer (NSCLC) who have a specific genetic mutation referred to as anaplastic lymphoma kinase (ALK) positivity. The Food and Drug Administration granted [...] Read more.
Alectinib, also known as Alecensa®, is prescribed for the therapeutic treatment of individuals diagnosed with metastatic non-small cell lung cancer (NSCLC) who have a specific genetic mutation referred to as anaplastic lymphoma kinase (ALK) positivity. The Food and Drug Administration granted regular approval to alectinib, a drug developed by Hoffmann-La Roche, Inc. (Basel, Switzerland)/Genentech, Inc. (South San Francisco, CA, USA), on 6 November 2017. The screening of the metabolic stability and identification of hazardous alarms within the chemical structure of ALC was conducted using the StarDrop software package (version 6.6), which incorporates the P450 metabolic module and DEREK software (KB 2018 1.1). The primary aim of this investigation was to develop a high-throughput and accurate LC-MS/MS technique for the quantification of ALC in the metabolic matrix (human liver microsomes; HLMs). The aforementioned methodology was subsequently employed to assess the metabolic stability of ALC in HLMs through in vitro tests, with the obtained results further validated using in silico software. The calibration curve of the ALC showed a linear correlation that exists within the concentration range from 1 to 3000 ng/mL. The LC-MS/MS approach that was recommended exhibited accuracy and precision levels for both inter-day and intra-day measurements. Specifically, the accuracy values ranged from −2.56% to 3.45%, while the precision values ranged from −3.78% to 4.33%. The sensitivity of the established approach was proved by its ability to adhere to an LLOQ of 0.82 ng/mL. The half-life (t1/2) and intrinsic clearance (Clint) of ALC were estimated to be 22.28 min and 36.37 mL/min/kg, correspondingly, using in vitro experiments. The ALC exhibited a moderate extraction ratio. The metabolic stability and safety properties of newly created derivatives can be enhanced by making modest adjustments to the morpholine and piperidine rings or by substituting the substituent, as per computational software. In in silico ADME prediction, ALC was shown to have poor water solubility and high gastrointestinal absorption along with inhibition of some cytochrome P450s (CYP2C19 and CYP2C9) without inhibition of others (CYP1A2, CYP3A4, and CYP2D6) and P-glycoprotein substrate. The study design that involves using both laboratory experiments and different in silico software demonstrates a novel and groundbreaking approach in the establishment and uniformization of LC-MS/MS techniques for the estimation of ALC concentrations, identifying structural alerts and the assessment of its metabolic stability. The utilization of this study strategy has the potential to be employed in the screening and optimization of prospective compounds during the drug creation process. This strategy may also facilitate the development of novel derivatives of the medicine that maintain the same biological action by targeted structural modifications, based on an understanding of the structural alerts included within the chemical structure of ALC. Full article
(This article belongs to the Special Issue ADME Properties in the Drug Delivery)
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