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ADME Properties in the Drug Delivery

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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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Keywords

drug delivery
ADMET
medicinal chemistry
pharmacokinetic properties

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Research

16 pages, 1859 KiB

Open AccessArticle

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 - 01 Nov 2023

Cited by 1 | Viewed by 1656

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 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

Open AccessArticle

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

Viewed by 1074

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 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 (t_1/2) and intrinsic clearance (Cl_int) 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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