Kinetic Characterization of Rat Hepatic Uptake of 16 Actively Transported Drugs

• DOI: 10.1124/dmd.111.040477
• Publication Date: 2011-07-06T02:26:13Z
• Authors: Yoshiyuki Yabe; Aleksandra Galetin; J. Brian Houston
• Keywords: Male; Biological Transport, Active; Facilitated Diffusion; Rats; 3. Good health; Rats, Sprague-Dawley; 03 medical and health sciences; 0302 clinical medicine; Liver; Hepatocytes; Animals; Drug Interactions; Pharmacokinetics

To explore the determinants of hepatic uptake, 16 compounds were investigated with different physicochemical and disposition characteristics, including five statins, three sartans, saquinavir, ritonavir, erythromycin, clarithromycin, nateglinide, repaglinide, fexofenadine, bosentan. Freshly isolated rat hepatocytes in suspension used oil-spin method to generate kinetic parameters. Clearances, via passive diffusion (<i>P</i>_diff) active uptake (CL_active, characterized by maximal rate <i>K</i>_m), estimated from initial data over a 0.01 100 μM concentration range. The <i>K</i>_m values had range 15-fold, 10 drugs &lt; (median 6 μM). Both CL_active <i>P</i>_diff ranged 100-fold 188 14 μl/min/10⁶ cells). Assessment relative contribution indicated that, at low concentrations (approximately 0.1 μM), process contributes &gt;80% overall for 13 drugs. Although high obtained ritonavir contributed predominantly uptake; contrast, permeability dominates transporter-mediated saquinavir full For bosentan processes equally important. Hepatocyte-to-medium unbound ratio was &gt;10 9 drugs, ranging 2 494 atorvastatin, respectively. Some showed extensive intracellular binding (fraction 0.01–0.6), which not correlated uptake. LogD_7.4 significantly extent but This study provides systematic assessment role process; implications findings are discussed.