title: Interaction of pharmaceutical excipients with organic cation transporters.
abstract: Increasing evidences have shown that many pharmaceutical excipients are not pharmacologically inert but instead have effects on several transport function of uptake and efflux drug transporters. Herein, we investigated whether the excipients frequently used in many drug formulations affect transport function of organic cation transporters (OCTs) that are responsible for elimination of cationic drugs. Our finding revealed that solubilizing agents, Tweens, showed the most significant effect rbOCT1/2-mediated [3H]-MPP+uptake in heterologous expressing cells. The haft inhibitory concentration (IC50) values of Tween 20, Tween 60, and Tween 80 for OCT1 were 85±1.12, 50±1.26, 106.00±1.20μg/ml, respectively, while the IC50values for OCT2 were 295±1.48, 42±1.15, 185±1.20μg/ml, respectively. The inhibitory effect of Tween 20, Tween 60 and Tween 80 on OCT2-mediated [3H]-MPP+uptake in the human renal proximal tubular cells (RPTEC/TERT1 cells) was found and the IC50values was similar to heterologous OCT2 expressing cells. Interestingly, Tween 20, Tween 60 and Tween 80 exhibited less inhibitory effect on OCT1 functions in HepG2 cells expressing OCT1 compared with heterologous OCT1 expressing cells. In addition, clearance of [3H]-MPP+was reduced in mice receiving Tween 20 compared with vehicle. The present study demonstrates that Tweens (solubilizing excipients) can inhibit the transport functions of OCT1 and OCT2, which play crucial roles for the pharmacokinetics, drug-drug interactions and tissue deposition of many cationic drugs.
authors.affiliation: Pharmaceutical Development of Green Innovations Group (PDGIG), Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, Thailand.
authors.forename: Sirima
authors.initials: S
authors.lastname: Soodvilai
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand; Research Center of Transport Proteins for Medical Innovation, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Sunhapas
authors.initials: S
authors.lastname: Soodvilai
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Varanuj
authors.initials: V
authors.lastname: Chatsudthipong
authors.affiliation: Pharmaceutical Development of Green Innovations Group (PDGIG), Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, Thailand.
authors.forename: Tanasait
authors.initials: T
authors.lastname: Ngawhirunpat
authors.affiliation: Pharmaceutical Development of Green Innovations Group (PDGIG), Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, Thailand.
authors.forename: Theerasak
authors.initials: T
authors.lastname: Rojanarata
authors.affiliation: Pharmaceutical Development of Green Innovations Group (PDGIG), Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, Thailand. Electronic address: opanasopit_p@su.ac.th.
authors.forename: Praneet
authors.initials: P
authors.lastname: Opanasopit
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000097:blood / Q000493:pharmacokinetics; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005079:Excipients / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors*; D011136:Polysorbates / Q000494:pharmacology*
chemical_list: D005079:Excipients; D027701:Organic Cation Transport Proteins; D011136:Polysorbates; D015655:1-Methyl-4-phenylpyridinium
keywords: Drug transporters; Excipients; Kidney; Liver; Tween