title: Relationship between the urinary excretion mechanisms of drugs and their physicochemical properties.
abstract: The purpose of this study was to clarify the relationship between the physicochemical properties of drugs and their urinary excretion mechanisms. Three hundred twenty-five drugs were classified into the reabsorption, intermediate, and secretion types based on their ratio of renal clearance to protein-unbound fraction glomerular filtration rate. Fifty percent of ionized and neutral drugs were the secretion and reabsorption types, respectively. The mean molecular weight of the neutral drugs was slightly smaller than those of the ionized drugs (296 vs. 330-368 g/mol). The reabsorption-type anionic drugs were characterized by their low molecular weights (mean value 269 g/mol) and the logarithmic measure of the acid dissociation constants (pKa s) greater than 4.5, whereas the secretion-type anionic drugs all had pKa s below 4.5. Cationic drugs with pKa s lower than 8.0 tended to be the reabsorption type. Some cationic drugs were classified as the secretion type, despite their high molecular weights (734-811 g/mol) and high log P values (3.1-5.3). The organic anion transporter (OAT)1 and OAT3 substrates were all secretion-type drugs. The same trend was observed for the substrates of organic cation transporter 2, multidrug and toxin extrusion, multidrug resistance-associated protein 4, and multidrug resistance 1/breast cancer resistance protein, but substantial fractions of the substrates were categorized as the intermediate or reabsorption types (9%-38%). This work provides a clue to the renal elimination mechanism of new chemical entities during drug development.
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Sumito
authors.initials: S
authors.lastname: Ito
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Ando
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ose
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kitamura
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ando
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D027682:Cation Transport Proteins / Q000378:metabolism; D005919:Glomerular Filtration Rate; D006801:Humans; D007668:Kidney / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism* / Q000652:urine*
chemical_list: D027682:Cation Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D004364:Pharmaceutical Preparations; C114338:organic anion transport protein 3
keywords: physicochemical; renal clearance; renal reabsorption; renal transport; transporters