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Contribution of Drug Metabolizing Enzymes and Transporters to Drug-Drug Interactions

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 May 2023) | Viewed by 3930

Special Issue Editors

Division of Pharmaceutics and Pharmacology, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
Interests: pharmacology; drug transporter; drug metabolism; pharmacokinetics; toxicology

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Guest Editor
Division of Outcomes and Translational Sciences, College of Pharmacy & Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
Interests: clinical pharmacology; transporter; oncology; chemotherapy-induced toxicity; pharmacokinetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Drug–drug interactions (DDIs) are an important consideration during the drug development process and the use of polypharmacy regimens in clinical practice; however, there remain many reports of unexpected, life-threatening DDIs associated with new therapeutics, such as tyrosine kinase inhibitors. Along with drug-metabolizing enzymes, transporters have recently emerged as critical determinants of pharmacokinetics and DDIs, and DDIs that alter the absorption, distribution, metabolism and excretion (ADME) protein function are known to impact therapeutic outcomes, including adverse events.

This Special Issue of Molecules aims to present an update of the latest findings regarding pharmacological important drug transporters and metabolizing enzymes that contribute to pharmacokinetics variability and drug interactions. We invite experts from the field to highlight the current progress in clinical or non-clinical settings, in order to meaure or predict pharmacokinetics variability and drug interactions. The knowledge gained from this Special Issue is expected to contribute to strategies that prevent life-threatening DDIs in patients with co-administered medications.

Dr. Yang Li
Dr. Shuiying Hu
Guest Editors

Manuscript Submission Information

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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 2700 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

  • pharmacokinetics
  • drug–drug interactions
  • drug development
  • drug transporters
  • drug metabolic enzymes
  • physiologically based pharmacokinetic modelling

Published Papers (2 papers)

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Research

14 pages, 1715 KiB  
Article
Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B
by Dominique A. Garrison, Yan Jin, Zahra Talebi, Shuiying Hu, Alex Sparreboom, Sharyn D. Baker and Eric D. Eisenmann
Molecules 2022, 27(20), 6815; https://doi.org/10.3390/molecules27206815 - 12 Oct 2022
Cited by 3 | Viewed by 1596
Abstract
Gilteritinib, an FDA-approved tyrosine kinase inhibitor approved for the treatment of relapsed/refractory FLT3-mutated acute myeloid leukemia, is primarily eliminated via CYP3A4-mediated metabolism, a pathway that is sensitive to the co-administration of known CYP3A4 inhibitors, such as itraconazole. However, the precise mechanism by which [...] Read more.
Gilteritinib, an FDA-approved tyrosine kinase inhibitor approved for the treatment of relapsed/refractory FLT3-mutated acute myeloid leukemia, is primarily eliminated via CYP3A4-mediated metabolism, a pathway that is sensitive to the co-administration of known CYP3A4 inhibitors, such as itraconazole. However, the precise mechanism by which itraconazole and other CYP3A-modulating drugs affect the absorption and disposition of gilteritinib remains unclear. In the present investigation, we demonstrate that pretreatment with itraconazole is associated with a significant increase in the systemic exposure to gilteritinib in mice, recapitulating the observed clinical drug–drug interaction. However, the plasma levels of gilteritinib were only modestly increased in CYP3A-deficient mice and not further influenced by itraconazole. Ensuing in vitro and in vivo studies revealed that gilteritinib is a transported substrate of OATP1B-type transporters, that gilteritinib exposure is increased in mice with OATP1B2 deficiency, and that the ability of itraconazole to inhibit OATP1B-type transport in vivo is contingent on its metabolism by CYP3A isoforms. These findings provide new insight into the pharmacokinetic properties of gilteritinib and into the molecular mechanisms underlying drug–drug interactions with itraconazole. Full article
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13 pages, 945 KiB  
Article
Steroid Resistance Associated with High MIF and P-gp Serum Levels in SLE Patients
by Alberto Beltrán-Ramírez, José Francisco Muñoz-Valle, Jorge I. Gamez-Nava, Ana Miriam Saldaña-Cruz, Laura Gonzalez-Lopez, Alejandro Padilla-Ortega, Francisco I. Arias-García, Gabriela Athziri Sánchez-Zuno, Cesar Arturo Nava-Valdivia, Juan Manuel Ponce-Guarneros, Jesús Jonathan García-Galindo and Edsaúl Emilio Perez-Guerrero
Molecules 2022, 27(19), 6741; https://doi.org/10.3390/molecules27196741 - 10 Oct 2022
Cited by 2 | Viewed by 1551
Abstract
Approximately 30% of patients with systemic lupus erythematosus (SLE) present steroid resistance (SR). Macrophage migration inhibition factor (MIF) and P-glycoprotein (P-gp) could be related to SR. This work aims to evaluate the relationship between MIF and P-pg serum levels in SR in SLE. [...] Read more.
Approximately 30% of patients with systemic lupus erythematosus (SLE) present steroid resistance (SR). Macrophage migration inhibition factor (MIF) and P-glycoprotein (P-gp) could be related to SR. This work aims to evaluate the relationship between MIF and P-pg serum levels in SR in SLE. Methods: Case–control study including 188 SLE patients who were divided into two groups (90 in the steroid-resistant group and 98 in the steroid-sensitive (SS) group) and 35 healthy controls. MIF and P-gp serum levels were determined by ELISA. Multivariable logistic regression and chi-squared automatic interaction detection (CHAID) were used to explore risk factors for SR. Results: The steroid-resistant group presented higher MIF and P-gp serum levels in comparison with the SS (p < 0.001) and reference (p < 0.001) groups. MIF correlated positively with P-gp (rho = 0.41, p < 0.001). MIF (≥15.75 ng/mL) and P-gp (≥15.22 ng/mL) were a risk factor for SR (OR = 2.29, OR = 5.27). CHAID identified high P-gp as the main risk factor for SR and high MIF as the second risk factor in those patients with low P-gp. Conclusions: An association between MIF and P-gp serum levels was observed in SR. CHAID identified P-gp ≥ 15.22 ng/mL as the main risk factor for SR. More studies are needed to validate these results. Full article
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