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 b changes, C t will change and Cu b will remain constant, whereas if CL int isvery high, Cu b will change and C b will remain constant.The present study defines the effects of a change in fu b on C b and Cu b over the whole CL int range. Computer simulations were undertaken which predicted that, for a given change in fu b ,absolute and relative changes in C b would decreasenonlinearly with increasing CL int, twhile the relative change in Cu b would increasewith CL int .The absolute change in Cub would be independent of CL int .Significant changes in Cb 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 μCi/mmol) was infused into the reservoir in a recycling system at 30 μmol/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.
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This study was supported by the National Health and Medical Research Council of Australia.
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Smallwood, R.H., Mihaly, G.W., Smallwood, R.A. et al. Effect of a protein binding change on unbound and total plasma concentrations for drugs of intermediate hepatic extraction. Journal of Pharmacokinetics and Biopharmaceutics 16, 529–542 (1988). https://doi.org/10.1007/BF01062383
- plasma protein binding displacement
- unbound fraction
- unbound concentration
- intrinsic clearance
- sodium taurocholate
- sodium oleate
- isolated perfused rat liver