Ex Situ Inhibition of Hepatic Uptake and Efflux Significantly Changes Metabolism: Hepatic Enzyme-Transporter Interplay

• DOI: 10.1124/jpet.103.061770
• Publication Date: 2004-02-25T22:12:55Z
• Authors: Yvonne Y. Lau; Chi-Yuan Wu; Hideaki Okochi; Leslie Z. Benet
• Keywords: Quinidine; Organic anion-transporting polypeptide; CYP3A; Efflux; P-glycoprotein

The disposition of digoxin and the influence organic anion transporting polypeptide (Oatp)2 inhibitor rifampicin P-glycoprotein (P-gp) quinidine on its hepatic were examined in isolated perfused rat liver. Livers from groups rats a recirculatory manner after bolus dose (10 μg), dual substrate for Oatp2 P-gp as well CYP3A. Perfusions also presence inhibitors: (100 μM) or μM). In all experiments, perfusate samples collected 60 min. Digoxin primary metabolite determined liver by liquid chromatography/mass spectrometry. area under curve (AUC) 0 to min was determined. AUC ± S.D. increased control (3880 210 nM·min) (5200 240 nM·min; <i>p</i> &lt; 0.01) decreased (3220 340 <i>P</i> 0.05). It is concluded that limits entrance reduced exposure CYP3A inhibiting basolateral uptake transport, whereas canalicular transport. These data emphasize importance efflux transporters drug metabolism.