Quantitative Prediction of Human Renal Clearance and Drug-Drug Interactions of Organic Anion Transporter Substrates Using In Vitro Transport Data: A Relative Activity Factor Approach.
Organic anion transporters (OATs) are important in the renal secretion, and thus, the clearance, of many drugs; and their functional change can result in pharmacokinetic variability. In this study, we applied transport rates measured in vitro using OAT-transfected human embryonic kidney cells to predict human renal secretory and total renal clearance of 31 diverse drugs. Selective substrates to OAT1 (tenofovir), OAT2 (acyclovir and ganciclovir), and OAT3 (benzylpenicillin, oseltamivir acid) were used to obtain relative activity factors (RAFs) for these individual transporters by relating in vitro transport clearance (after physiologic scaling) to in vivo secretory clearance. Using the estimated RAFs (0.64, 7.3, and 4.1, respectively, for OAT1, OAT2, and OAT3, respectively) and the in vitro active clearances, renal secretory clearance and total renal clearance were predicted with average fold errors (AFEs) of 1.89 and 1.40, respectively. The results show that OAT3-mediated transport play a predominant role in renal secretion for 22 of the 31 drugs evaluated. This mechanistic static approach was further applied to quantitatively predict renal drug-drug interactions (AFE ∼1.6) of the substrate drugs with probenecid, a clinical probe OAT inhibitor. In conclusion, the proposed in vitro-in vivo extrapolation approach is the first comprehensive attempt toward mechanistic modeling of renal secretory clearance based on routinely employed in vitro cell models.
Pharmacokinetics, Pharmacodynamics, and Metabolism Department, Pfizer Inc., Groton, Connecticut (S.M., M.A.P., B.F., M.V.V.) and Cambridge Massachusetts (D.A.T., J.L.).
Sumathy
S
Mathialagan
Pharmacokinetics, Pharmacodynamics, and Metabolism Department, Pfizer Inc., Groton, Connecticut (S.M., M.A.P., B.F., M.V.V.) and Cambridge Massachusetts (D.A.T., J.L.).
Mary A
MA
Piotrowski
Pharmacokinetics, Pharmacodynamics, and Metabolism Department, Pfizer Inc., Groton, Connecticut (S.M., M.A.P., B.F., M.V.V.) and Cambridge Massachusetts (D.A.T., J.L.).
David A
DA
Tess
Pharmacokinetics, Pharmacodynamics, and Metabolism Department, Pfizer Inc., Groton, Connecticut (S.M., M.A.P., B.F., M.V.V.) and Cambridge Massachusetts (D.A.T., J.L.).
Bo
B
Feng
Pharmacokinetics, Pharmacodynamics, and Metabolism Department, Pfizer Inc., Groton, Connecticut (S.M., M.A.P., B.F., M.V.V.) and Cambridge Massachusetts (D.A.T., J.L.).
John
J
Litchfield
Pharmacokinetics, Pharmacodynamics, and Metabolism Department, Pfizer Inc., Groton, Connecticut (S.M., M.A.P., B.F., M.V.V.) and Cambridge Massachusetts (D.A.T., J.L.) manthena.v.varma@pfizer.com.
Manthena V
MV
Varma
D000212:Acyclovir / Q000493:pharmacokinetics; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D004347:Drug Interactions; D015774:Ganciclovir / Q000493:pharmacokinetics; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008954:Models, Biological; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053139:Oseltamivir / Q000493:pharmacokinetics; D010400:Penicillin G / Q000493:pharmacokinetics; D011339:Probenecid / Q000494:pharmacology; D065667:Renal Elimination / Q000502:physiology*; D000068698:Tenofovir / Q000493:pharmacokinetics; D014162:Transfection
D000900:Anti-Bacterial Agents; D000998:Antiviral Agents; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C490280:SLC22A7 protein, human; C114338:organic anion transport protein 3; D053139:Oseltamivir; D000068698:Tenofovir; D015774:Ganciclovir; D011339:Probenecid; D010400:Penicillin G; D000212:Acyclovir