title: Novel Method to Predict In Vivo Liver-to-Plasma Kpuufor OATP Substrates Using Suspension Hepatocytes.
abstract: The ability to predict human liver-to-plasma unbound partition coefficient (Kpuu) is of great importance to estimate unbound liver concentration, develop PK/PD relationships, predict efficacy and toxicity in the liver, and model the drug-drug interaction potential for drugs that are asymmetrically distributed into the liver. A novel in vitro method has been developed to predict in vivo Kpuuwith good accuracy using cryopreserved suspension hepatocytes in InVitroGRO HI media with 4% BSA. Validation was performed using six OATP substrates with rat in vivo Kpuudata from i.v. infusion studies where a steady state was achieved. Good in vitro-in vivo correlation (IVIVE) was observed as the in vitro Kpuuvalues were mostly within 2-fold of in vivo KpuuGood KpuuIVIVE in human was also observed with in vivo Kpuudata of dehydropravastatin from positron emission tomography and in vivo Kpuudata from PK/PD modeling for pravastatin and rosuvastatin. Under the specific Kpuuassay conditions, the drug-metabolizing enzymes and influx/efflux transporters appear to function at physiologic levels. No scaling factors are necessary to predict in vivo Kpuufrom in vitro data. The novel in vitro Kpuumethod provides a useful tool in drug discovery to project in vivo Kpuu.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut (K.R., Ji.L., M.N., S.R., W.H., K.A., R.E.K., L.D.); Cambridge, Massachusetts (Z.L., Jo.L.).
authors.forename: Keith
authors.initials: K
authors.lastname: Riccardi
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut (K.R., Ji.L., M.N., S.R., W.H., K.A., R.E.K., L.D.); Cambridge, Massachusetts (Z.L., Jo.L.).
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut (K.R., Ji.L., M.N., S.R., W.H., K.A., R.E.K., L.D.); Cambridge, Massachusetts (Z.L., Jo.L.).
authors.forename: Zhenhong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut (K.R., Ji.L., M.N., S.R., W.H., K.A., R.E.K., L.D.); Cambridge, Massachusetts (Z.L., Jo.L.).
authors.forename: Mark
authors.initials: M
authors.lastname: Niosi
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut (K.R., Ji.L., M.N., S.R., W.H., K.A., R.E.K., L.D.); Cambridge, Massachusetts (Z.L., Jo.L.).
authors.forename: Sangwoo
authors.initials: S
authors.lastname: Ryu
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut (K.R., Ji.L., M.N., S.R., W.H., K.A., R.E.K., L.D.); Cambridge, Massachusetts (Z.L., Jo.L.).
authors.forename: Wenyi
authors.initials: W
authors.lastname: Hua
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut (K.R., Ji.L., M.N., S.R., W.H., K.A., R.E.K., L.D.); Cambridge, Massachusetts (Z.L., Jo.L.).
authors.forename: Karen
authors.initials: K
authors.lastname: Atkinson
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut (K.R., Ji.L., M.N., S.R., W.H., K.A., R.E.K., L.D.); Cambridge, Massachusetts (Z.L., Jo.L.).
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Kosa
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut (K.R., Ji.L., M.N., S.R., W.H., K.A., R.E.K., L.D.); Cambridge, Massachusetts (Z.L., Jo.L.).
authors.forename: John
authors.initials: J
authors.lastname: Litchfield
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut (K.R., Ji.L., M.N., S.R., W.H., K.A., R.E.K., L.D.); Cambridge, Massachusetts (Z.L., Jo.L.) li.di@pfizer.com.
authors.forename: Li
authors.initials: L
authors.lastname: Di
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D055808:Drug Discovery / Q000379:methods*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D027361:Organic Anion Transporters / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000097:blood* / Q000378:metabolism; D011237:Predictive Value of Tests; D051381:Rats; D017208:Rats, Wistar; D013379:Substrate Specificity
chemical_list: D027361:Organic Anion Transporters; D004364:Pharmaceutical Preparations