Impaired renal function is associated with important changes in the binding of some drugs to plasma proteins. In some cases the tissue binding of drugs is also affected.
albumin binding sites by organic molecules that accumulate in uremia. As described in Chapter 3, reductions in the protein binding of acidic drugs result in increases in their distribution volume. In addition, the elimination clearance of restrictively eliminated drugs is increased. However, protein binding changes do not affect distribution volume or clearance estimates when they are referenced to unbound drug concentrations. For restrictively eliminated drugs, the term intrinsic clearance is used to describe the clearance that would be observed in the absence of any protein binding restrictions. As discussed in Chapter 7, the clearance of restrictively eliminated drugs, when referenced to total drug concentrations, simply equals the product of the unbound fraction of drug (fu) and this intrinsic clearance (CL(nt ):
Phenytoin is an acidic, restrictively eliminated drug that can be used to illustrate some of the changes in drug distribution and elimination that occur in patients with impaired renal function. In patients with normal renal function, 92% of the phenytoin in plasma is protein bound. However, the percentage that is unbound or "free" rises from 8% in these individuals to 16%, or more, in hemodialysis-dependent patients. In a study comparing phenytoin pharmacokinetics in normal subjects and uremic patients, Odar-Cederlof and Borga (26) administered a single low dose of this drug so that first-order kinetics were approximated. The results shown in Table 5.3 can be inferred from their study. The uremic patients had an increase in distribution volume that was consistent with the observed decrease in phenytoin binding to plasma proteins. The threefold increase in hepatic clearance that was observed in these patients also was primarily the result of decreased phenytoin protein binding. Although intrinsic hepatic clearance also appeared to be increased in the uremic patients, the difference did not reach statistical significance at the P = 0.05 level.
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