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Pharmaceutics
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Pharmacokinetics and Drug–Drug Interactions of Novel Psychotropic Drugs
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Pharmacokinetics and Drug–Drug Interactions of Novel Psychotropic Drugs

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

Deadline for manuscript submissions: closed (31 December 2024) | Viewed by 13369

Special Issue Editors

Dr. Przemysław J. Danek

E-Mail Website
Guest Editor
Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krakow, Poland
Interests: psychopharmacology; antidepressants; antipsychotics; drug development; drug metabolism; drug–drug interactions; cytochrome P450
Dr. Anna Haduch

E-Mail Website
Guest Editor
Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland
Interests: psychopharmacology; brain metabolism; cytochrome P450; drug metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Psychotropic drugs (antipsychotics, antidepressants, mood stabilizers, anxiolytics) have been playing an increasing role in the treatment of mental disorders for over half a century. They have offered substantial relief from some debilitating symptoms like auditory hallucinations, depression, and excessive mood fluctuations. Psychotropics are used as monotherapy, as well as adjunctive or augmentation therapy in several psychiatric disorders. Pharmacotherapy with psychotropic drugs is carried out for months/years, very often in combination with drugs from other pharmacological groups. Concomitant therapy with psychotropics may result in pharmacokinetic interactions that produce adverse reactions. The majority of clinically relevant pharmacokinetic drug–drug interactions with psychotropics occur as a consequence of drug-induced changes in hepatic metabolism. The most frequently reported cases of drug–drug interactions include the modulation of psychotropic drugs on drug-metabolizing enzymes and transporters and the causative pharmacokinetic effect of co-administered therapeutic drugs that are substrates for drug-metabolizing enzymes and transporters.

Therefore, this Special Issue aims to highlight the pharmacokinetics and drug interactions of novel psychotropic drugs and their mechanistic understanding concerning drug-metabolizing enzymes and drug transporters.

In this Special Issue of Pharmaceutics, we invite you to contribute original research articles or reviews on all aspects of the theme “Pharmacokinetics and Drug–Drug Interactions of Novel Psychotropic Drugs”. Expert articles describing new aspects of pharmacokinetics, ADME, drug–drug interactions, or new aspects of novel psychotropic drug actions are highly welcome.

Dr. Przemysław J. Danek
Dr. Anna Haduch
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

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

  • psychiatric disorders
  • new drugs
  • psychotropic drugs
  • antidepressants
  • antipsychotics
  • drug development
  • therapy
  • targets

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Published Papers (6 papers)

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Research

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14 pages, 2279 KiB  
Article
Evaluation of the Drug–Drug Interaction Potential of Cannabidiol Against UGT2B7-Mediated Morphine Metabolism Using Physiologically Based Pharmacokinetic Modeling
by Shelby Coates, Keti Bardhi, Bhagwat Prasad and Philip Lazarus
Pharmaceutics 2024, 16(12), 1599; https://doi.org/10.3390/pharmaceutics16121599 - 16 Dec 2024
Viewed by 1298
Abstract
Background: Morphine is a commonly prescribed opioid analgesic used to treat chronic pain. Morphine undergoes glucuronidation by UDP-glucuronosyltransferase (UGT) 2B7 to form morphine-3-glucuronide and morphine-6-glucuronide. Morphine is the gold standard for chronic pain management and has a narrow therapeutic index. Reports have shown [...] Read more.
Background: Morphine is a commonly prescribed opioid analgesic used to treat chronic pain. Morphine undergoes glucuronidation by UDP-glucuronosyltransferase (UGT) 2B7 to form morphine-3-glucuronide and morphine-6-glucuronide. Morphine is the gold standard for chronic pain management and has a narrow therapeutic index. Reports have shown that chronic pain patients have increasingly used other supplements to treat their chronic pain, including cannabidiol (CBD). Up to 50% of chronic pain patients report that they co-use cannabis with their prescribed opioid for pain management, including morphine. Previous work has shown that cannabidiol is a potent inhibitor of UGT2B7, including morphine-mediated metabolism. Co-use of morphine and CBD may result in unwanted drug–drug interactions (DDIs). Methods: Using available physiochemical and clinical parameters, morphine and CBD physiologically based pharmacokinetic (PBPK) models were developed and validated in both healthy and cirrhotic populations. Models for the two populations were then combined to predict the severity and clinical relevance of the potential DDIs during coadministration of both morphine and CBD in both healthy and hepatic-impaired virtual populations. Results: The predictive DDI model suggests that a ~5% increase in morphine exposure is to be expected in healthy populations. A similar increase in exposure of morphine is predicted in severe hepatic-impaired populations with an increase of ~10. Conclusions: While these predicted increases in morphine exposure are below the Food and Drug Administration’s cutoff (1.25-fold increase), morphine has a narrow therapeutic index and a 5–10% increase in exposure may be clinically relevant. Future clinical studies are needed to fully characterize the clinical relevance of morphine-related DDIs. Full article
(This article belongs to the Special Issue Pharmacokinetics and Drug–Drug Interactions of Novel Psychotropic Drugs)
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14 pages, 1303 KiB  
Article
Cannabinoid-Induced Inhibition of Morphine Glucuronidation and the Potential for In Vivo Drug–Drug Interactions
by Shelby Coates, Keti Bardhi and Philip Lazarus
Pharmaceutics 2024, 16(3), 418; https://doi.org/10.3390/pharmaceutics16030418 - 18 Mar 2024
Cited by 2 | Viewed by 3221
Abstract
Opioids are commonly prescribed for the treatment of chronic pain. Approximately 50% of adults who are prescribed opioids for pain co-use cannabis with their opioid treatment. Morphine is primarily metabolized by UDP-glucuronosyltransferase (UGT) 2B7 to an inactive metabolite, morphine-3-glucuronide (M3G), and an active [...] Read more.
Opioids are commonly prescribed for the treatment of chronic pain. Approximately 50% of adults who are prescribed opioids for pain co-use cannabis with their opioid treatment. Morphine is primarily metabolized by UDP-glucuronosyltransferase (UGT) 2B7 to an inactive metabolite, morphine-3-glucuronide (M3G), and an active metabolite, morphine-6-glucuronide (M6G). Previous studies have shown that major cannabis constituents including Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) inhibit major UGT enzymes. To examine whether cannabinoids or their major metabolites inhibit morphine glucuronidation by UGT2B7, in vitro assays and mechanistic static modeling were performed with these cannabinoids and their major metabolites including 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC), 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (11-COOH-THC), 7-hydroxy-cannabidiol (7-OH-CBD), and 7-carboxy-cannabidiol (7-COOH-CBD). In vitro assays with rUGT-overexpressing microsomes and human liver microsomes showed that THC and CBD and their metabolites inhibited UGT2B7-mediated morphine metabolism, with CBD and THC exhibiting the most potent Ki,u values (0.16 µM and 0.37 µM, respectively). Only 7-COOH-CBD exhibited no inhibitory activity against UGT2B7-mediated morphine metabolism. Static mechanistic modeling predicted an in vivo drug–drug interaction between morphine and THC after inhaled cannabis, and between THC, CBD, and 7-OH-CBD after oral consumption of cannabis. These data suggest that the co-use of these agents may lead to adverse drug events in humans. Full article
(This article belongs to the Special Issue Pharmacokinetics and Drug–Drug Interactions of Novel Psychotropic Drugs)
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17 pages, 1881 KiB  
Article
Cannabinoid-Induced Stereoselective Inhibition of R-S-Oxazepam Glucuronidation: Cannabinoid–Oxazepam Drug Interactions
by Keti Bardhi, Shelby Coates, Gang Chen and Philip Lazarus
Pharmaceutics 2024, 16(2), 243; https://doi.org/10.3390/pharmaceutics16020243 - 7 Feb 2024
Cited by 1 | Viewed by 2323
Abstract
Benzodiazepines (BZDs) such as oxazepam are commonly prescribed depressant drugs known for their anxiolytic, hypnotic, muscle relaxant, and anticonvulsant effects and are frequently used in conjunction with other illicit drugs including cannabis. Oxazepam is metabolized in an enantiomeric-specific manner by glucuronidation, with S-oxazepam [...] Read more.
Benzodiazepines (BZDs) such as oxazepam are commonly prescribed depressant drugs known for their anxiolytic, hypnotic, muscle relaxant, and anticonvulsant effects and are frequently used in conjunction with other illicit drugs including cannabis. Oxazepam is metabolized in an enantiomeric-specific manner by glucuronidation, with S-oxazepam metabolized primarily by UGT2B15 and R-oxazepam glucuronidation mediated by both UGT 1A9 and 2B7. The goal of the present study was to evaluate the potential inhibitory effects of major cannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), and major THC metabolites, 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (11-COOH-THC), on the UGT-mediated metabolism of R- and S-oxazepam. The cannabinoids and metabolites were screened as inhibitors of R- and S-oxazepam glucuronidation in microsomes isolated from HEK293 cells overexpressing individual UGT enzymes (rUGTs). The IC50 values were determined in human liver microsomes (HLM), human kidney microsomes (HKM), and rUGTs and utilized to estimate the nonspecific, binding-corrected Ki (Ki,u) values and predict the area under the concentration–time curve ratio (AUCR). The estimated Ki,u values observed in HLM for S- and R-oxazepam glucuronidation by CBD, 11-OH-THC, and THC were in the micromolar range (0.82 to 3.7 µM), with the Ki,u values observed for R-oxazepam glucuronidation approximately 2- to 5-fold lower as compared to those observed for S-oxazepam glucuronidation. The mechanistic static modeling predicted a potential clinically significant interaction between oral THC and CBD with oxazepam, with the AUCR values ranging from 1.25 to 3.45. These data suggest a pharmacokinetic drug–drug interaction when major cannabinoids like CBD or THC and oxazepam are concurrently administered. Full article
(This article belongs to the Special Issue Pharmacokinetics and Drug–Drug Interactions of Novel Psychotropic Drugs)
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Review

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21 pages, 754 KiB  
Review
Pharmacokinetics of Non-Psychotropic Phytocannabinoids
by Mariana Lacerda, Andreia Carona, Sara Castanheira, Amílcar Falcão, Joana Bicker and Ana Fortuna
Pharmaceutics 2025, 17(2), 236; https://doi.org/10.3390/pharmaceutics17020236 - 12 Feb 2025
Cited by 1 | Viewed by 1133
Abstract
Cannabinoids are widely recognized for their potential therapeutic effects, making them significant and valuable candidates for medical research and applications across various fields. This review aims to analyze the pharmacokinetics of Cannabidiol (CBD), Cannabigerol (CBG), and Cannabichromene (CBC), along with their corresponding acidic [...] Read more.
Cannabinoids are widely recognized for their potential therapeutic effects, making them significant and valuable candidates for medical research and applications across various fields. This review aims to analyze the pharmacokinetics of Cannabidiol (CBD), Cannabigerol (CBG), and Cannabichromene (CBC), along with their corresponding acidic forms, Cannabidiolic acid (CBDA), Cannabigerolic acid (CBGA), and Cannabichromenic acid (CBCA). Among these cannabinoids, CBD is the most extensively studied. Nevertheless, research involving all the mentioned cannabinoids has shown that their pharmacokinetic parameters are highly variable, depending significantly on factors such as dose, formulation, route of administration, and diet. Furthermore, challenges such as brain penetration and first-pass metabolism have been highlighted. In conclusion, this review demonstrates significant progress in understanding the pharmacokinetics of non-psychotropic cannabinoids. However, it also underscores the need for further research, particularly on CBG, CBC, and their respective acidic forms, with the most significant gap being in clinical investigations. Expanding these studies is essential to facilitate their optimized use in medical treatments. Full article
(This article belongs to the Special Issue Pharmacokinetics and Drug–Drug Interactions of Novel Psychotropic Drugs)
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17 pages, 483 KiB  
Review
Challenges and Opportunities in Managing Geriatric Depression: The Role of Personalized Medicine and Age-Appropriate Therapeutic Approaches
by Agnieszka Jaros, Filip Rybakowski, Judyta Cielecka-Piontek, Magdalena Paczkowska-Walendowska, Bogusław Czerny, Adam Kamińki, Rasha Wafaie Mahmoud Elsorady and Agnieszka Bienert
Pharmaceutics 2024, 16(11), 1397; https://doi.org/10.3390/pharmaceutics16111397 - 30 Oct 2024
Cited by 1 | Viewed by 2105
Abstract
The global aging population has experienced rapid growth in recent decades, leading to an increased prevalence of psychiatric disorders, particularly depression, among older adults. Depression in the geriatric population is often compounded by chronic physical conditions and various psychosocial factors, significantly impacting their [...] Read more.
The global aging population has experienced rapid growth in recent decades, leading to an increased prevalence of psychiatric disorders, particularly depression, among older adults. Depression in the geriatric population is often compounded by chronic physical conditions and various psychosocial factors, significantly impacting their quality of life. The main question raised in this review is as follows: how can personalized medicine and age-appropriate therapeutic approaches improve the management of geriatric depression? This paper explores the epidemiology of geriatric depression, highlighting the influence of gender, race, and socioeconomic status on its prevalence. The classification and diagnosis of geriatric depressive disorders, based on ICD-11 and DSM-5 criteria, reveal the complexity of managing these conditions in older adults. Personalized medicine (PM) emerges as a promising approach, focusing on tailoring treatments to the individual’s genetic, clinical, and environmental characteristics. However, the application of PM in this demographic faces challenges, particularly in the context of pharmaceutical forms. The need for age-appropriate drug delivery systems is critical, given the prevalence of polypharmacy and issues such as dysphagia among the older patients. This study emphasizes the importance of developing patient-centric formulations to enhance the effectiveness of personalized therapy in geriatric patients. Full article
(This article belongs to the Special Issue Pharmacokinetics and Drug–Drug Interactions of Novel Psychotropic Drugs)
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Other

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21 pages, 1268 KiB  
Systematic Review
Pharmacokinetics of Psilocybin: A Systematic Review
by Shakila Meshkat, Huda Al-Shamali, Argyrios Perivolaris, Trusha Tullu, Richard J. Zeifman, Yanbo Zhang, Lisa Burback, Olga Winkler, Andrew Greenshaw, Muhammad Ishrat Husain, Amy C. Reichelt, Eric Vermetten, Manish K. Jha, Rakesh Jetly, Raimar Loebenberg and Venkat Bhat
Pharmaceutics 2025, 17(4), 411; https://doi.org/10.3390/pharmaceutics17040411 - 25 Mar 2025
Viewed by 1960
Abstract
Background: Psilocybin has shown promise in therapeutic applications for mental disorders. Understanding the pharmacokinetics of psilocybin and its active metabolite psilocin is crucial for optimizing its clinical use and minimizing adverse effects. Methods: This systematic review involved a comprehensive search across MEDLINE, APA [...] Read more.
Background: Psilocybin has shown promise in therapeutic applications for mental disorders. Understanding the pharmacokinetics of psilocybin and its active metabolite psilocin is crucial for optimizing its clinical use and minimizing adverse effects. Methods: This systematic review involved a comprehensive search across MEDLINE, APA PsycINFO, and Embase databases, from inception to December 2024, identifying original studies that investigated the pharmacokinetics of psilocybin. Results: Fourteen studies met the inclusion criteria: eight laboratory-based and six clinical studies. Laboratory studies used animal models or in vitro systems, while clinical studies included 112 healthy human participants. Psilocybin is rapidly dephosphorylated to psilocin, which is absorbed with Tmax values ranging from 1.8 to 4 h following oral administration. Cmax varied dose-dependently, from 8.2 ± 2.8 ng/mL (plasma) to 871 ng/mL (urine). One study reported psilocin bioavailability at 52.7 ± 20%. The volume of distribution was extensive, ranging from 277 ± 92 L to 1016 L, suggesting significant tissue distribution. Psilocin metabolism is primarily mediated by CYP2D6 and CYP3A4, with secondary contributions from monoamine oxidase A. It undergoes further hepatic biotransformation into 4-hydroxyindole-3-acetic acid and 4-hydroxytryptophol. Elimination half-life varied across studies, ranging from 1.5 to 4 h. Conclusions: Psilocybin pharmacokinetics demonstrate significant variability based on dosage, route, and species. CYP enzymes play a critical role in its metabolism, highlighting the potential for drug–drug interactions. These findings underscore the importance of further research to elucidate psilocybin’s pharmacokinetic profile, which is assessed in vivo by its active metabolite psilocin. Full article
(This article belongs to the Special Issue Pharmacokinetics and Drug–Drug Interactions of Novel Psychotropic Drugs)
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