Organic Anion Transporter 2-Mediated Hepatic Uptake Contributes to the Clearance of High-Permeability-Low-Molecular-Weight Acid and Zwitterion Drugs: Evaluation Using 25 Drugs
| Autor: | Jian Lin, Sumathy Mathialagan, Manthena V.S. Varma, David A. Tess, Anthony Carlo, Emi Kimoto, Mark Niosi, Laurie Tylaska |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Organic anion transporter 1
Pharmacology Nateglinide Organic Anion Transporters Sodium-Independent 030226 pharmacology & pharmacy Models Biological Permeability Cell Line 03 medical and health sciences 0302 clinical medicine Pharmacokinetics medicine Humans biology Chemistry Membrane Transport Proteins Biological Transport Metabolism Transfection In vitro Molecular Weight Kinetics HEK293 Cells Liver Pharmaceutical Preparations Cell culture 030220 oncology & carcinogenesis biology.protein Microsome Hepatocytes Microsomes Liver Molecular Medicine medicine.drug |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 367(2) |
| ISSN: | 1521-0103 |
| Popis: | High-permeability-low-molecular-weight acids/zwitterions [i.e., extended clearance classification system class 1A (ECCS 1A) drugs] are considered to be cleared by metabolism with a minimal role of membrane transporters in their hepatic clearance. However, a marked disconnect in the in vitro-in vivo (IVIV) translation of hepatic clearance is often noted for these drugs. Metabolic rates measured using human liver microsomes and primary hepatocytes tend to underpredict. Here, we evaluated the role of organic anion transporter 2 (OAT2)-mediated hepatic uptake in the clearance of ECCS 1A drugs. For a set of 25 ECCS 1A drugs, in vitro transport activity was assessed using transporter-transfected cells and primary human hepatocytes. All but two drugs showed substrate affinity to OAT2, whereas four (bromfenac, entacapone, fluorescein, and nateglinide) also showed OATP1B1 activity in transfected cells. Most of these drugs (21 of 25) showed active uptake by plated human hepatocytes, with rifamycin SV (pan-transporter inhibitor) reducing the uptake by about 25%-95%. Metabolic turnover was estimated for 19 drugs after a few showed no measurable substrate depletion in liver microsomal incubations. IVIV extrapolation using in vitro data was evaluated to project human hepatic clearance of OAT2-alone substrates considering 1) uptake transport only, 2) metabolism only, and 3) transporter-enzyme interplay (extended clearance model). The transporter-enzyme interplay approach achieved improved prediction accuracy (average fold error = 1.9 and bias = 0.93) compared with the other two approaches. In conclusion, this study provides functional evidence for the role of OAT2-mediated hepatic uptake in determining the pharmacokinetics of several clinically important ECCS 1A drugs. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|