Interactions between cyazofamid and human drug transporters

• Published in: Journal of biochemical and molecular toxicology 2020-04, Vol.34 (4), p.e22459-n/a
• Main Authors: Song, Im‐Sook, Jeong, Hyeon‐Uk, Choi, Min‐Koo, Kwon, Mihwa, Shin, Yongho, Kim, Jeong Han, Lee, Hye‐Suk
• Format: Article
• Language: English
• Subjects: Animals; ATP-Binding Cassette Transporters - antagonists & inhibitors; ATP-Binding Cassette Transporters - metabolism; Biological Transport; Breast cancer; Caco-2 Cells; Cell Membrane Permeability; cyazofamid; drug interaction; Drug Interactions; drug transporters; Fungicides; Fungicides, Industrial - metabolism; Fungicides, Industrial - pharmacokinetics; Fungicides, Industrial - pharmacology; Glycoproteins; HEK293 Cells; Humans; Imidazoles - metabolism; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Inhibitory Concentration 50; intestinal permeability; Intestine; Intestines - physiology; LLC-PK1 Cells; Membrane Transport Proteins - metabolism; Multidrug resistance; Oct-2 protein; Oct-4 protein; Organic Anion Transporters - antagonists & inhibitors; Organic Anion Transporters - metabolism; Organic anion transporting polypeptide; Organic Cation Transport Proteins - antagonists & inhibitors; Organic Cation Transport Proteins - metabolism; Organic cation transporter; Permeability; Polypeptides; Proteins; Substrates; Sulfonamides - metabolism; Sulfonamides - pharmacokinetics; Sulfonamides - pharmacology; Swine; Toxicity
• ISSN: 1095-6670; 1099-0461
• DOI: 10.1002/jbt.22459

We aimed to investigate the intestinal permeability and interaction of cyazofamid with clinically important transporters. The intestinal permeability of cyazofamid was low (0.21 ± 0.02 cm/s), and it is a substrate for P‐glycoprotein (P‐gp) with a Km value of 83.1 μM, indicated that P‐gp in the intestinal lumen could serve as a protective barrier to this fungicide. Cyazofamid was not a substrate for clinically important transporters. However, cyazofamid inhibited organic cation transporter 3 (OCT3) and OAT1, with IC50 values of 1.54 and 17.3 μM, respectively, but could not result in OAT3‐ and OAT1‐mediated cyazofamid‐drug interactions because of its low plasma concentration. Cyazofamid poorly interacted with OCT1, OCT2, organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, P‐gp, breast cancer resistance‐related protein, and multidrug resistance‐related protein 2. In conclusion, the interactions of cyazofamid with human drug transporters have been evaluated as part of the safety assessment. Given its low intestinal permeability and poor interaction with human drug transporters, cyazofamid might not cause serious toxicity or adverse events.