Haloperidol is an inhibitor but not substrate for MDR1/P-glycoprotein

• Published in: Journal of pharmacy and pharmacology Vol. 58; no. 12; p. 1617
• Main Authors: Iwaki, Koichi, Sakaeda, Toshiyuki, Kakumoto, Mikio, Nakamura, Tsutomu, Komoto, Chiho, Okamura, Noboru, Nishiguchi, Kohshi, Shiraki, Takashi, Horinouchi, Masanori, Okumura, Katsuhiko
• Format: Journal Article
• Language: English
• Published: England 01.12.2006
• Subjects: Animals; Antipsychotic Agents - metabolism; Antipsychotic Agents - pharmacology; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological Transport - drug effects; Digoxin - metabolism; Dose-Response Relationship, Drug; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Haloperidol - metabolism; Haloperidol - pharmacology; Humans; LLC-PK1 Cells; Swine; Time Factors; Transfection; Tritium; Vinblastine - metabolism
• ISSN: 0022-3573
• DOI: 10.1211/jpp.58.12.0008

The involvement of the multidrug resistant transporter MDR1/P-glycoprotein in the penetration of haloperidol into the brain and absorption in the intestine was investigated to examine its role in inter/intra-individual variability, using the porcine kidney epithelial cell line LLC-PK(1) and its MDR1-overexpressing transfectant, LLC-GA5-COL150. The inhibitory effect of haloperidol on other MDR1 substrates was also investigated in terms of the optimization of haloperidol-based pharmacotherapy. The transepithelial transport of [(3)H]haloperidol did not differ between the two cell lines, and vinblastine, a typical MDR1 substrate, had no effect on the transport, suggesting that haloperidol is not a substrate for MDR1, and it is unlikely that MDR function affects haloperidol absorption and brain distribution, and thereby the response to haloperidol. However, haloperidol was found to have an inhibitory effect on the MDR1-mediated transport of [(3)H]digoxin and [(3)H]vinblastine with an IC50 value of 7.84+/-0.76 and 3.60+/-0.64 microM, respectively, suggesting that the intestinal absorption, not distribution into the brain, of MDR1 substrate drugs could be altered by the co-administration of haloperidol in the clinical setting, although further clinical studies are needed.