title: Multiple Linear Regression Analysis Indicates Association of P-Glycoprotein Substrate or Inhibitor Character with Bitterness Intensity, Measured with a Sensor.
abstract: P-glycoprotein (P-gp) regulates absorption of many drugs in the gastrointestinal tract and their accumulation in tumor tissues, but the basis of substrate recognition by P-gp remains unclear. Bitter-tasting phenylthiocarbamide, which stimulates taste receptor 2 member 38 (T2R38), increases P-gp activity and is a substrate of P-gp. This led us to hypothesize that bitterness intensity might be a predictor of P-gp-inhibitor/substrate status. Here, we measured the bitterness intensity of a panel of P-gp substrates and nonsubstrates with various taste sensors, and used multiple linear regression analysis to examine the relationship between P-gp-inhibitor/substrate status and various physical properties, including intensity of bitter taste measured with the taste sensor. We calculated the first principal component analysis score (PC1) as the representative value of bitterness, as all taste sensor's outputs shared significant correlation. The P-gp substrates showed remarkably greater mean bitterness intensity than non-P-gp substrates. We found that Km value of P-gp substrates were correlated with molecular weight, log P, and PC1 value, and the coefficient of determination (R(2) ) of the linear regression equation was 0.63. This relationship might be useful as an aid to predict P-gp substrate status at an early stage of drug discovery.
authors.affiliation: Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Gunma, 370-0033, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yano
authors.affiliation: Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Gunma, 370-0033, Japan.
authors.forename: Suzune
authors.initials: S
authors.lastname: Mita
authors.affiliation: Department of Drug Absorption and Pharmacokinetics, Tohoku Pharmaceutical University, Sendai, Miyagi, 981-8558, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Morimoto
authors.affiliation: Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Hyogo, 663-8179, Japan.
authors.forename: Tamami
authors.initials: T
authors.lastname: Haraguchi
authors.affiliation: Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Gunma, 370-0033, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Arakawa
authors.affiliation: Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Hyogo, 663-8179, Japan.
authors.forename: Miyako
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo, Kyoto, 606-8501, Japan.
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Yamashita
authors.affiliation: Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Hyogo, 663-8179, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Uchida
authors.affiliation: Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Gunma, 370-0033, Japan.
authors.forename: Takuo
authors.initials: T
authors.lastname: Ogihara
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000465:Algorithms; D015374:Biosensing Techniques; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D016014:Linear Models; D008970:Molecular Weight; D025341:Principal Component Analysis; D012995:Solubility; D013379:Substrate Specificity; D013649:Taste / Q000187:drug effects*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins
keywords: Log P; Multivariate analysis; P-glycoprotein; Physicochemical properties; Transporters; absorption; bitterness intensity; correlation efficient; inhibition; multiple linear regression analysis; solubility; substrate specificity