Comparison of Methods for Estimating Unbound Intracellular-to-Medium Concentration Ratios in Rat and Human Hepatocytes Using Statins
| Autor: | Kazuya Maeda, Kazuaki Ikejiri, Hiroyuki Kusuhara, Kota Toshimoto, Tomohisa Nakada, Takashi Yoshikado, Yuichi Sugiyama |
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| Rok vydání: | 2017 |
| Předmět: |
Male
medicine.medical_specialty Organic Anion Transporters Pharmaceutical Science Hepatic clearance 030226 pharmacology & pharmacy Permeability Membrane Potentials Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Internal medicine medicine Animals Humans Rosuvastatin Calcium Pitavastatin Pravastatin Pharmacology Chemistry Biological Transport Rats Sprague dawley Passive permeability Endocrinology Liver metabolism Liver 030220 oncology & carcinogenesis Hepatocytes Quinolines Hydroxymethylglutaryl-CoA Reductase Inhibitors Intracellular medicine.drug |
| Zdroj: | Drug Metabolism and Disposition. 45:779-789 |
| ISSN: | 1521-009X 0090-9556 |
| Popis: | It is essential to estimate concentrations of unbound drugs inside the hepatocytes to predict hepatic clearance, efficacy, and toxicity of the drugs. The present study was undertaken to compare predictability of the unbound hepatocyte-to-medium concentration ratios (Kp,uu) by two methods based on the steady-state cell-to-medium total concentration ratios at 37°C and on ice (Kp,uu,ss) and based on their initial uptake rates (Kp,uu,V0). Poorly metabolized statins were used as test drugs because of their concentrative uptake via organic anion-transporting polypeptides. Kp,uu,ss values of these statins provided less interexperimental variation than the Kp,uu,V0 values, because only data at longer time are required for Kp,uu,ss Kp,uu,V0 values for pitavastatin, rosuvastatin, and pravastatin were 1.2- to 5.1-fold Kp,uu,ss in rat hepatocytes; Kp,uu,V0 values in human hepatocytes also tended to be larger than corresponding Kp,uu,ss To explain these discrepancies, theoretical values of Kp,uu,ss and Kp,uu,V0 were compared with true Kp,uu (Kp,uu,true), considering the inside-negative membrane potential and ionization of the drugs in hepatocytes and medium. Membrane potentials were approximately -30 mV in human hepatocytes at 37°C and almost abolished on ice. Theoretical equations considering the membrane potentials indicate that Kp,uu,ss values for the statins are 0.85- to 1.2-fold Kp,uu,true, whereas Kp,uu,V0 values are 2.2- to 3.1-fold Kp,uu,true, depending on the ratio of the passive permeability of the ionized to nonionized forms. In conclusion, Kp,uu,ss values of anions are similar to Kp,uu,true when the inside-negative membrane potential is considered. This suggests that Kp,uu,ss is preferable for estimating the concentration of unbound drugs inside the hepatocytes. |
| Databáze: | OpenAIRE |
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