In vitro evidence suggesting that the toll-like receptor 7 and 8 agonist resiquimod (R-848) unlikely affects drug levels of co-administered compounds

• Verfasst von: Theile, Dirk [VerfasserIn]
• Verfasst von: Wagner, Lelia [VerfasserIn]
• Verfasst von: Haefeli, Walter E. [VerfasserIn]
• Verfasst von: Weiß, Johanna [VerfasserIn]
• Titel: In vitro evidence suggesting that the toll-like receptor 7 and 8 agonist resiquimod (R-848) unlikely affects drug levels of co-administered compounds
• Verf.angabe: Dirk Theile, Lelia Wagner, Walter E. Haefeli, Johanna Weiss
• E-Jahr: 2021
• Jahr: 2 April 2021
• Umfang: 7 S.
• Fussnoten: Gesehen am 04.03.2022
• Titel Quelle: Enthalten in: European journal of pharmaceutical sciences
• Ort Quelle: New York, NY [u.a.] : Elsevier, 1993
• Jahr Quelle: 2021
• Band/Heft Quelle: 162(2021) vom: 1. Juli, Artikel-ID 105826, Seite 1-7
• ISSN Quelle: 1879-0720
• DOI: doi:10.1016/j.ejps.2021.105826
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: CYP3A4
• Sach-SW: Drug transporter
• Sach-SW: Nuclear factor kappa B
• Sach-SW: Pharmacokinetic interactions
• Sach-SW: Pregnane x receptor
• Sach-SW: Resiquimod
• K10plus-PPN: 1794687963

Abstract

Resiquimod (R-848) is an immune response modifier activating toll-like receptor 7 and 8. Its potential to cause pharmacokinetic interactions with concurrently administered drugs is unknown. To study the time course of the effect of resiquimod in LS180 cells as a model for intestinal tissue, luciferase-based reporter gene assays and reverse transcription polymerase chain reaction were used to investigate whether resiquimod affects the activities of nuclear factor kappa B (NF-ĸB), pregnane x receptor (PXR) or the transcription of selected central genes for drug disposition (cytochrome P-450 isozyme 3A4 (CYP3A4), CYP1A1, UDP-glucuronosyltransferase 1A1 (UGT1A1), ATP-binding cassette transporters ABCC2, ABCB1). Its impact on the activities of organic anion transporting polypeptides 1 or 3 (OATP1B1/3), breast cancer resistance protein (BCRP), P-glycoprotein (P-gp) or CYP3A4 was evaluated using fluorescence- or luminescence-based activity assays. Resiquimod irrelevantly increased NF-ĸB activity after 2 h (1 µM: 1.07-fold, P = 0.0188; 10 µM: 1.09-fold, P = 0.0142), and diminished it after 24 h (1 µM: 0.64-fold, P < 0.0001; 10 µM: 0.68-fold, P < 0.0001) and 30 h (10 µM: 0.68-fold, P = 0.0003). Concurrently, PXR activity after 24 h was marginally increased by 10 µM (1.05-fold, P = 0.0019). Resiquimod did not alter mRNA expression levels, activities of uptake or efflux transporters, or CYP3A4 activity. Given the marginal effects on NF-ĸB, PXR, expression levels of selected PXR target genes, and activities of important drug transporters and CYP3A4 in vitro, resiquimod is not expected to cause major pharmacokinetic drug-drug interactions in vivo.