Effects of Anticholinergic Drugs Used for the Therapy of Overactive Bladder on P-Glycoprotein Activity

• Published in: Biological & pharmaceutical bulletin Vol. 42; no. 12; pp. 1996 - 2001
• Main Authors: Wakuda, Hirokazu, Okura, Takashi, Maruyama-Fumoto, Kana, Kagota, Satomi, Ito, Yoshihiko, Miyauchi-Wakuda, Shino, Otani, Naoyuki, Uemura, Naoto, Yamada, Shizuo, Shinozuka, Kazumasa
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.12.2019; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Adenosine triphosphatase; Adenosine Triphosphatases - metabolism; anticholinergic drug; Anticholinergics; ATP Binding Cassette Transporter, Subfamily B - metabolism; Caco-2 Cells; Cell membranes; Cholinergic Antagonists - pharmacology; Cholinergic Antagonists - therapeutic use; Confocal microscopy; Cyclosporins; Drugs; Glycoproteins; Humans; Metabolites; overactive bladder; P-Glycoprotein; Protein transport; Rhodamine; Urinary Bladder, Overactive - drug therapy; P-glycoprotein; anticholinergic drug; overactive bladder
• ISSN: 0918-6158; 1347-5215; 1347-5215
• DOI: 10.1248/bpb.b19-00407

We evaluated the effects of anticholinergic drugs principally used for the therapy of overactive bladder (OAB) on the activity of P-glycoprotein, an efflux transport protein, in Caco-2 cells. The time-dependent changes in the fluorescence of residual rhodamine 123, a P-glycoprotein activity marker, in the apical region of Caco-2 cells were measured in the presence of anticholinergic drugs using time-lapse confocal laser scanning microscopy. The effect of anticholinergic drugs on human P-glycoprotein ATPase activity was also measured. The fluorescence of residual rhodamine 123 in untreated Caco-2 cells decreased over time. The gradual decrease in the fluorescence was significantly inhibited by treatment with cyclosporine A, darifenacin, and trospium. In contrast, oxybutynin, N-desethyl-oxybutynin (DEOB), propiverine, and its active metabolites (M-1, M-2), imidafenacin, solifenacin, or tolterodine had little effect on the efflux of rhodamine 123. P-Glycoprotein ATPase activity was increased by darifenacin. Darifenacin and trospium reduced the rhodamine 123 transfer across the apical cell membrane. These data suggest that darifenacin and trospium interact with P-glycoprotein. Additionally, darifenacin influenced P-glycoprotein ATPase activity. These results suggest that darifenacin may be a substrate of P-glycoprotein. This study is the first paper to test simultaneously the effects of 10 anticholinergic drugs used currently for the therapy of OAB, on the P-glycoprotein.