Effect of a protein binding change on unbound and total plasma concentrations for drugs of intermediate hepatic extraction

For substances eliminated from blood by the liver, the effect of a change in unbound fraction of drug (fu_b)on steady state total (C_b)and unbound (Cu_b)blood concentrations has hitherto only been considered for the two limiting cases, i.e., at the upper and lower extremes of hepatic intrinsic clearance (CL_int).For a substance of very low CL_int,if fu_bchanges, C_twill change and Cu_bwill remain constant, whereas if CL_int isvery high, Cu_bwill change and C_bwill remain constant.The present study defines the effects of a change in fu_bon C_band Cu_bover the whole CL_intrange. Computer simulations were undertaken which predicted that, for a given change in fu_b,absolute and relative changes in C_bwould decreasenonlinearly with increasing CL_{int, twhile the relative change in} Cu_{b would} increasewith CL_int.The absolute change in Cu_bwould be independent of CL_int.Significant changes in C_b and Cu_{b would be observed at intermediate values of} CL_{int not just at the high and low extremes. These theoretical predictions were investigated experimentally in the isolated perfused rat liver by examining the effects of a change in} fu_{b of sodium taurocholate a substance with intermediate} CL_int (such that at fu_b=0.27,hepatic extraction ratio=0.71) induced by concurrent administration of sodium oleate. Sodium 24-¹⁴C-taurocholate (specific activity 52 Ci/mmol) was infused into the reservoir in a recycling system at 30 mol/hr for 105 min (n=6). At 45 min a bolus dose of sodium oleate (50 mmol) was administered to the reservoir, followed by a constant infusion of 143 mmol/hr for 1 hr. Following the administration of oleate, taurocholate fu_{b fell promptly by 55% (0.27–0.12). There was a relative increase of taurocholate} C_{b of 22.7% and a relative decrease in} Cu_{b of 45.4%, in accordance with the simulations (p<0.05). We conclude that important changes in unbound steady-state concentration, the pharmacologically active moiety, can occur upon changes in unbound fraction with compounds of intermediate hepatic intrinsic clearance}.This study was supported by the National Health and Medical Research Council of Australia.