title: Toward a unified model of passive drug permeation II: the physiochemical determinants of unbound tissue distribution with applications to the design of hepatoselective glucokinase activators.
abstract: In this work, we leverage a mathematical model of the underlying physiochemical properties of tissues and physicochemical properties of molecules to support the development of hepatoselective glucokinase activators. Passive distribution is modeled via a Fick-Nernst-Planck approach, using in vitro experimental data to estimate the permeability of both ionized and neutral species. The model accounts for pH and electrochemical potential across cellular membranes, ionization according to Henderson-Hasselbalch, passive permeation of the neutral species using Fick's law, and passive permeation of the ionized species using the Nernst-Planck equation. The mathematical model of the physiochemical system allows derivation of a single set of parameters governing the distribution of drug molecules across multiple conditions both in vitro and in vivo. A case study using this approach in the development of hepatoselective glucokinase activators via organic anion-transporting polypeptide-mediated hepatic uptake and impaired passive distribution to the pancreas is described. The results for these molecules indicate the permeability penalty of the ionized form is offset by its relative abundance, leading to passive pancreatic exclusion according to the Nernst-Planck extension of Fickian passive permeation. Generally, this model serves as a useful construct for drug discovery scientists to understand subcellular exposure of acids or bases using specific physiochemical properties.
authors.affiliation: Systems Modeling and Simulation (A.G., T.S.M.), Cardiovascular and Metabolic Disease Research Unit (J.L., D.O.S.), Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Cambridge, Massachusetts; Enzymology and Transporters, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Groton, Connecticut (B.F., M.V.V., C.R., R.S.); and World Wide Medicinal Chemistry, Cambridge, Massachusetts (M.T., C.R.W.G.) avijit@physics.drexel.edu.
authors.forename: Avijit
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Systems Modeling and Simulation (A.G., T.S.M.), Cardiovascular and Metabolic Disease Research Unit (J.L., D.O.S.), Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Cambridge, Massachusetts; Enzymology and Transporters, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Groton, Connecticut (B.F., M.V.V., C.R., R.S.); and World Wide Medicinal Chemistry, Cambridge, Massachusetts (M.T., C.R.W.G.).
authors.forename: Tristan S
authors.initials: TS
authors.lastname: Maurer
authors.affiliation: Systems Modeling and Simulation (A.G., T.S.M.), Cardiovascular and Metabolic Disease Research Unit (J.L., D.O.S.), Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Cambridge, Massachusetts; Enzymology and Transporters, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Groton, Connecticut (B.F., M.V.V., C.R., R.S.); and World Wide Medicinal Chemistry, Cambridge, Massachusetts (M.T., C.R.W.G.).
authors.forename: John
authors.initials: J
authors.lastname: Litchfield
authors.affiliation: Systems Modeling and Simulation (A.G., T.S.M.), Cardiovascular and Metabolic Disease Research Unit (J.L., D.O.S.), Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Cambridge, Massachusetts; Enzymology and Transporters, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Groton, Connecticut (B.F., M.V.V., C.R., R.S.); and World Wide Medicinal Chemistry, Cambridge, Massachusetts (M.T., C.R.W.G.).
authors.forename: Manthema V
authors.initials: MV
authors.lastname: Varma
authors.affiliation: Systems Modeling and Simulation (A.G., T.S.M.), Cardiovascular and Metabolic Disease Research Unit (J.L., D.O.S.), Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Cambridge, Massachusetts; Enzymology and Transporters, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Groton, Connecticut (B.F., M.V.V., C.R., R.S.); and World Wide Medicinal Chemistry, Cambridge, Massachusetts (M.T., C.R.W.G.).
authors.forename: Charles
authors.initials: C
authors.lastname: Rotter
authors.affiliation: Systems Modeling and Simulation (A.G., T.S.M.), Cardiovascular and Metabolic Disease Research Unit (J.L., D.O.S.), Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Cambridge, Massachusetts; Enzymology and Transporters, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Groton, Connecticut (B.F., M.V.V., C.R., R.S.); and World Wide Medicinal Chemistry, Cambridge, Massachusetts (M.T., C.R.W.G.).
authors.forename: Renato
authors.initials: R
authors.lastname: Scialis
authors.affiliation: Systems Modeling and Simulation (A.G., T.S.M.), Cardiovascular and Metabolic Disease Research Unit (J.L., D.O.S.), Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Cambridge, Massachusetts; Enzymology and Transporters, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Groton, Connecticut (B.F., M.V.V., C.R., R.S.); and World Wide Medicinal Chemistry, Cambridge, Massachusetts (M.T., C.R.W.G.).
authors.forename: Bo
authors.initials: B
authors.lastname: Feng
authors.affiliation: Systems Modeling and Simulation (A.G., T.S.M.), Cardiovascular and Metabolic Disease Research Unit (J.L., D.O.S.), Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Cambridge, Massachusetts; Enzymology and Transporters, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Groton, Connecticut (B.F., M.V.V., C.R., R.S.); and World Wide Medicinal Chemistry, Cambridge, Massachusetts (M.T., C.R.W.G.).
authors.forename: Meihua
authors.initials: M
authors.lastname: Tu
authors.affiliation: Systems Modeling and Simulation (A.G., T.S.M.), Cardiovascular and Metabolic Disease Research Unit (J.L., D.O.S.), Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Cambridge, Massachusetts; Enzymology and Transporters, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Groton, Connecticut (B.F., M.V.V., C.R., R.S.); and World Wide Medicinal Chemistry, Cambridge, Massachusetts (M.T., C.R.W.G.).
authors.forename: Cris R W
authors.initials: CR
authors.lastname: Guimaraes
authors.affiliation: Systems Modeling and Simulation (A.G., T.S.M.), Cardiovascular and Metabolic Disease Research Unit (J.L., D.O.S.), Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Cambridge, Massachusetts; Enzymology and Transporters, Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Groton, Connecticut (B.F., M.V.V., C.R., R.S.); and World Wide Medicinal Chemistry, Cambridge, Massachusetts (M.T., C.R.W.G.).
authors.forename: Dennis O
authors.initials: DO
authors.lastname: Scott
mesh_terms: D000818:Animals; D001693:Biological Transport, Active; D002460:Cell Line; D015195:Drug Design; D020536:Enzyme Activators / Q000737:chemistry / Q000493:pharmacokinetics*; D005941:Glucokinase / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D015394:Molecular Structure; D009132:Muscles / Q000187:drug effects / Q000378:metabolism*; D009525:Niacin / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics; D009539:Nicotinic Acids / Q000737:chemistry / Q000493:pharmacokinetics*; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D010539:Permeability; D051381:Rats; D014018:Tissue Distribution
chemical_list: C000597952:6-(2-(4-(cyclobutanesulfonyl)-1H-imidazol-1-yl)-3-cyclopentylpropanamido)pyridine-3-carboxylic acid; D020536:Enzyme Activators; D007093:Imidazoles; D009539:Nicotinic Acids; D009525:Niacin; C571532:6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid; D005941:Glucokinase