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Mechanisms of Drug Interactions: Pharmacodynamics and Pharmacokinetics

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

Deadline for manuscript submissions: 10 June 2025 | Viewed by 6850

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Prof. Dr. Marta Karaźniewicz-Łada

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Department of Physical Pharmacy and Pharmacokinetics, Collegium Pharmaceuticum, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland
Interests: vitamin D; bioanalysis of endogenous compounds; HPLC-MS/MS; method validation; pharmacokinetics; pharmacogenetics
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Dr. Agnieszka Karbownik

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Department of Clinical Pharmacy and Biopharmacy, Poznan University of Medical Sciences, 3 Rokietnicka Str., 60-806 Poznań, Poland
Interests: pharmacokinetics; drug-drug interaction; tyrosine kinase inhibitor; blood-brain barrier; zebrafish
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Dr. Danuta Szkutnik-Fiedler

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Dear Colleagues,

Drug interactions occur when a change in drug activity is observed, and can be pharmacokinetic (PK) or pharmacodynamic (PD). In addition, we observe drug–drug, drug–dietary supplement, drug–disease, drug–microbiome, and drug–food interactions. Pharmacokinetic interactions occur when one drug alters another drug's absorption, distribution, metabolism, or excretion. This type of reaction can vary between patients and requires individual management. Pharmacodynamic interactions occur between drugs with similar or opposite pharmacological effects. The underlying mechanisms involve competition at molecular or cellular sites of action, and the effects are generally common to related drugs. The occurrence of interactions between the drugs a patient takes can have an adverse effect on the action of the drugs and the patient's health. Treatment is not effective if the effect of the drugs is weakened and/or their action modified. On the other hand, an increase in the plasma concentration of a therapeutic substance and its prolonged residence in the human body can lead to adverse effects specific to the drug, but with greater intensity and a greater probability. Such effects can be dangerous to the patient's health or even life-threatening.

This Special Issue welcomes studies on the mechanisms underlying drug interactions, their clinical and economic significance, and practical, evidence-based options for the safe and effective management of the consequences of drug interactions.

Prof. Dr. Marta Karaźniewicz-Łada
Dr. Agnieszka Karbownik
Dr. Danuta Szkutnik-Fiedler
Guest Editors

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Keywords

drug interactions
pharmacokinetics
pharmacodynamics
ADME

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Published Papers (6 papers)

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Research

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15 pages, 1540 KiB

Open AccessArticle

Vitamin D Status Determines Metformin Action on Gonadotropin Levels in Postmenopausal Women with Subclinical Hyperthyroidism

by Robert Krysiak, Karolina Kowalcze, Witold Szkróbka and Bogusław Okopień

Pharmaceutics 2025, 17(4), 442; https://doi.org/10.3390/pharmaceutics17040442 - 30 Mar 2025

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Abstract

Background/Objectives: The gonadotropin-lowering effects of metformin were found to be more pronounced in the case of coexisting hyperthyroidism and absent in patients with hypovitaminosis D. Thus, the aim of the current study was to determine whether vitamin D status determines pituitary effects of metformin in individuals with thyroid hyperfunction and elevated gonadotropin levels. Methods: This prospective cohort study included three matched groups of postmenopausal women with hyperthyroidism and prediabetes: women with 25-hydroxyvitamin D levels between 50 and 75 nmol/L (uncompensated vitamin D insufficiency), women with 25-hydroxyvitamin D levels between 75 and 150 nmol/L receiving exogenous calciferol due to previously diagnosed vitamin D deficiency/insufficiency (compensated vitamin D deficiency/insufficiency), and calciferol-naïve subjects with 25-hydroxyvitamin D levels between 75 and 150 nmol/L (the control group). Over the entire study period (six months), all the women were treated with metformin. At the beginning and at the end of this study, we determined 25-hydroxyvitamin D, glucose homeostasis markers, gonadotropins, estradiol, progesterone, TSH, free thyroid hormones, prolactin, ACTH, and IGF-1. Results: Before metformin treatment, except for the 25-hydroxyvitamin D levels, there were no between-group differences in the investigated markers. In all the study groups, metformin reduced plasma glucose, HOMA1-IR, glycated hemoglobin, and FSH, but these effects were more pronounced in both groups of women with normal vitamin D status than in women with uncompensated vitamin D insufficiency. The decrease in LH concentration was observed only in patients with compensated vitamin D deficiency/insufficiency and in the control group. There were no differences between the baseline and follow-up levels of the remaining hormones. The impact of metformin on gonadotropin concentrations positively correlated with their baseline values, free thyroid hormone levels, 25-hydroxyvitamin D levels, and metformin-induced changes in HOMA1-IR. Conclusions: Our findings suggest that low vitamin D status impairs the gonadotropin-lowering effects of metformin in individuals with hyperthyroidism. Full article

(This article belongs to the Special Issue Mechanisms of Drug Interactions: Pharmacodynamics and Pharmacokinetics)

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21 pages, 4001 KiB

Open AccessArticle

Pharmacokinetics of Snake Antivenom Following Intravenous and Intramuscular Administration in Envenomed Large Animal Model

by Erika Gamulin, Sanja Mateljak Lukačević, Maja Lang Balija, Ana Smajlović, Dražen Vnuk, Jadranka Gulan Harcet, Maja Tomičić, Ana Hećimović, Beata Halassy and Tihana Kurtović

Pharmaceutics 2025, 17(2), 212; https://doi.org/10.3390/pharmaceutics17020212 - 7 Feb 2025

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Abstract

Background: The parenteral administration of antivenoms is the mainstay in snakebite envenoming therapy. The standardized protocol does not exist, but it is agreed that the intravenous (i.v.) route is more effective than the others, especially the intramuscular (i.m.) route, based on the monitoring of venom/antivenom pharmacokinetics in the systemic circulation. Recent evidence suggests that the lymphatic system may be crucial in abolishing venom action. Methods: A preclinical study was performed to determine the optimal administration route with emphasis on venom/antivenom interplay in both the blood and lymph of experimentally envenomed sheep. Timed level measurements were used to compare the antivenom effect on the decrement of venom quantities in both relevant body compartments. Hematological and coagulation parameters, as well as proportions of developed anti-antivenom IgGs, were evaluated. Results: The i.m. antivenom resulted in faster and greater lymphatic absorption and complete neutralization of the venom, whereas the i.v. antivenom only slowed its absorption. The total amount of venom reaching the lymph (AUC_0-t) was two times lower after i.m. administration. In the systemic circulation, i.m. antivenom had a lower peak concentration (c_max) and a longer time to reach it (t_max). However, the total venom exposure was three times lower than with i.v. antivenom. Irrespective of the treatment approach, both groups showed improvement in blood disorders with no significant difference in humoral response against equine F(ab’)₂ fragments. Conclusions: I.m. administration proved to be a viable option for the snakebite management. Full article

(This article belongs to the Special Issue Mechanisms of Drug Interactions: Pharmacodynamics and Pharmacokinetics)

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15 pages, 2722 KiB

Open AccessArticle

LC-MS/MS-Based Concurrent Quantification of Cannabidiol and Melatonin in Mouse Plasma to Elucidate Complex PK Interactions

by Mengran Wang, Wenpeng Zhang, Xia Wu, Lingchao Wang, Cong Li, Chunyan Liu and Xiaomei Zhuang

Pharmaceutics 2024, 16(12), 1511; https://doi.org/10.3390/pharmaceutics16121511 - 25 Nov 2024

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Abstract

Objective: This study aimed to develop a quantitative analytical method for the simultaneous determination of cannabidiol (CBD) and melatonin (MT) in mouse plasma using the protein precipitation method coupled with LC-MS/MS. Additionally, this study sought to investigate the impact of CBD on the pharmacokinetics of MT in mice using this method. Methods: Mouse plasma samples were precipitated with acetonitrile and analyzed using a Kromasil 100-5-C8 (2.1 × 50 mm) column. Following a single administration, thirty male ICR mice were randomly assigned to five groups: MT 2 mg/kg intravenously (i.v.), MT 10 mg/kg orally (p.o.), MT + CBD (10 + 10) mg/kg p.o., MT + CBD (10 + 40) mg/kg p.o., and MT 10 mg/kg p.o. followed by CBD 2 mg/kg i.v. Pharmacokinetic parameters were calculated using a non-compartmental model and analyzed to investigate the interactions of CBD with MT. Results: The calibration curves for CBD and MT were linear over the range of 2 to 1000 ng/mL. Co-administration of a high dose of CBD (40 mg/kg) orally reduced the C_max of MT (10 mg/kg) to 57% of the control, while the area under the curve from 0.5 to 8 h (AUC_(0.5–8h)) was 2.85-fold that of the MT-only group. When CBD (2 mg/kg) was administered intravenously alongside MT orally, the AUC_(0.5–8h) was 1.54 times that of MT given orally alone. The AUC of CBD was positively correlated with the AUC of the distribution and elimination phases of MT, while the C_max of CBD negatively correlated with the C_max of MT. Conclusions: The developed LC-MS/MS method is robust and suitable for pharmacokinetic studies involving CBD and MT. The in vivo effects of CBD on MT pharmacokinetics are complex. High oral doses of CBD inhibit both the intestinal absorption and metabolic clearance of MT, resulting in a more smooth PK profile. Full article

(This article belongs to the Special Issue Mechanisms of Drug Interactions: Pharmacodynamics and Pharmacokinetics)

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14 pages, 1741 KiB

Open AccessArticle

A Pharmacokinetic Study of the Interaction Between Regorafenib and Paracetamol in Male Rats

by Agnieszka Karbownik, Danuta Szkutnik-Fiedler, Filip Otto, Anna Wolc, Tomasz Grabowski, Zuzanna Maciejewska, Aleksandra Borycka and Edyta Szałek

Pharmaceutics 2024, 16(11), 1387; https://doi.org/10.3390/pharmaceutics16111387 - 28 Oct 2024

Cited by 1 | Viewed by 1269

Abstract

Background: In clinical practice, the prevalent problem of polypharmacy could result in increased risks of drug–drug interactions. Regorafenib (REG) is commonly co-administered with paracetamol (PA) as a treatment protocol in cancer patients with pain therapy. Purpose: This study aimed to demonstrate the effect of paracetamol on the pharmacokinetic parameters of regorafenib and its metabolites following a single administration of both substances in rats. Additionally, the influence of REG and its metabolites on the pharmacokinetics of paracetamol was also determined. Methods: Twenty-four rats were divided randomly into three groups: REG group (II_REG, regorafenib 20 mg/kg, n = 8), PA group (III_PA, paracetamol 100 mg/kg, n = 8), and REG+PA co-administration group (I_REG+PA, REG 20 mg/kg and PA 100 mg/kg, n = 8). The concentrations of regorafenib, regorafenib-N-oxide (M-2), and N-desmethyl-regorafenib-N-oxide (M-5) were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS). The plasma concentrations of PA and its glucuronide (GPA) and sulfate (SPA) metabolites were measured using the validated high-performance liquid chromatography method with ultraviolet detection (HPLC–UV). The pharmacokinetic parameters were calculated using a non-compartmental model. The statistical evaluation was performed in the SAS program. Results: After the administration of PA, the C_max and AUC_0–∞ of REG increased by 890% and 1140%, respectively; for M-2, they increased by 220% and 170%, and for M-5, by 2130% and 1730% (C_max and AUC_0–∞, respectively). A difference in the ratio of M-2/REG for AUC_0–∞ and C_max between the groups was observed, but not for M-5/REG. The AUC_0–∞ for PA and GPA decreased by 20.7% and 51.1%, respectively, when PA was co-administered with REG. But the AUC_0–∞ for SPA increased by 91.35% in the I_REG+PA group. A difference in the ratio of GPA/PA for C_max and for SPA/PA for AUC_0–t and AUC_0–∞ between the groups was observed. Conclusions: Paracetamol increased the plasma exposure of regorafenib, M-2, and M-5, which may exacerbate the drug’s side effects. In contrast, REG reduced paracetamol exposure and contributed to its faster elimination, which may reduce the analgesic and antipyretic effects of paracetamol. These findings suggest clinical relevance for oncology patients requiring analgesic treatment. Full article

(This article belongs to the Special Issue Mechanisms of Drug Interactions: Pharmacodynamics and Pharmacokinetics)

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13 pages, 748 KiB

Open AccessArticle

The Association between Vitamin D Status and the Impact of Metformin on Hypothalamic–Pituitary–Thyroid Axis Activity in Women with Subclinical Hypothyroidism

by Robert Krysiak, Karolina Kowalcze, Witold Szkróbka and Bogusław Okopień

Pharmaceutics 2024, 16(8), 1093; https://doi.org/10.3390/pharmaceutics16081093 - 20 Aug 2024

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Abstract

Metformin inhibits enhanced secretion of anterior pituitary hormones. Its impact on prolactin and gonadotropin concentrations is absent in individuals with hypovitaminosis D. The aim of this prospective cohort study was to investigate whether vitamin D status determines the effect of metformin on hypothalamic–pituitary–thyroid axis activity in levothyroxine-naïve women. The study included three groups of women of reproductive age with subclinical non-autoimmune hypothyroidism, which were matched for age, thyroid-stimulating hormone (TSH) concentration, and insulin sensitivity: untreated women with vitamin D deficiency/insufficiency (group A), women effectively supplemented with exogenous calciferol (group B), and untreated women with normal 25-hydroxyvitamin D concentrations (25OHD) (group C). Owing to concomitant type 2 diabetes or prediabetes, all subjects were treated with metformin. Concentrations of 25OHD, TSH, total and free thyroid hormones, glucose, insulin, glycated hemoglobin (HbA_1c), prolactin, and peripheral markers of thyroid hormone action were assayed before metformin treatment and six months later. Based on hormone concentration, structure parameters of thyroid homeostasis were calculated. Except for 25OHD concentrations, there were no between-group differences in baseline values of the measured variables. Metformin reduced glucose, the homeostatic model assessment 1 of insulin resistance ratio (HOMA1-IR), and HbA_1c in all study group, but these effects were less pronounced in group A than in the remaining groups. The reduction in TSH and Jostel’s index was observed only in groups B and C, and its degree correlated with baseline TSH concentrations, baseline 25OHD concentrations, and the degree of improvement in HOMA1-IR. The drug did not affect circulating levels of 25OHD, free and total thyroid hormones, prolactin, other structure parameters of thyroid homeostasis, and markers of thyroid hormone action. The obtained results allow us to conclude that low vitamin D status in young women mitigates the impact of metformin on thyrotroph secretory function. Full article

(This article belongs to the Special Issue Mechanisms of Drug Interactions: Pharmacodynamics and Pharmacokinetics)

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46 pages, 1601 KiB

Open AccessEditor’s ChoiceReview

Drug-Drug Interactions Between HIV Antivirals and Concomitant Drugs in HIV Patients: What We Know and What We Need to Know

by Emanuela De Bellis, Danilo Donnarumma, Adele Zarrella, Salvatore Maria Mazzeo, Annarita Pagano, Valentina Manzo, Ines Mazza, Francesco Sabbatino, Graziamaria Corbi, Pasquale Pagliano, Amelia Filippelli and Valeria Conti

Pharmaceutics 2025, 17(1), 31; https://doi.org/10.3390/pharmaceutics17010031 - 28 Dec 2024

Cited by 1 | Viewed by 1450

Abstract

Highly active antiretroviral therapy has led to a significant increase in the life expectancy of people living with HIV. The trade-off is that HIV-infected patients often suffer from comorbidities that require additional treatment, increasing the risk of Drug-Drug Interactions (DDIs), the clinical relevance of which has often not been determined during registration trials of the drugs involved. Therefore, it is important to identify potential clinically relevant DDIs in order to establish the most appropriate therapeutic approaches. This review aims to summarize and analyze data from studies published over the last two decades on DDI-related adverse clinical outcomes involving anti-HIV drugs and those used to treat comorbidities. Several studies have examined the pharmacokinetics and tolerability of different drug combinations. Protease inhibitors, followed by nonnucleoside reverse transcriptase inhibitors and integrase inhibitors have been recognized as the main players in DDIs with antivirals used to control co-infection, such as Hepatitis C virus, or with drugs commonly used to treat HIV comorbidities, such as lipid-lowering agents, proton pump inhibitors and anticancer drugs. However, the studies do not seem to be consistent with regard to sample size and follow-up, the drugs involved, or the results obtained. It should be noted that most of the available studies were conducted in healthy volunteers without being replicated in patients. This hampered the assessment of the clinical burden of DDIs and, consequently, the optimal pharmacological management of people living with HIV. Full article

(This article belongs to the Special Issue Mechanisms of Drug Interactions: Pharmacodynamics and Pharmacokinetics)

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