Protein binding of drugs in plasma, interstitial fluid and tissues: Effect on pharmacokinetics

Abstract

Drug binding in the interstitial fluid as well as in the plasma must be taken into account when considering the pharmacokinetics of drugs which are highly bound to plasma proteins and have a relatively small apparent volume of distribution (V). The half-life and apparent volume of distribution of such a drug can be affected significantly by changes in the extent of binding of the drug in both the plasma and the interstitial fluid. An alteration in the fraction of drug in the tissues which is unbound will primarily affect the pharmacokinetics of drugs which have a relatively large apparent volume of distribution. The effect of changes in the plasma free fraction of drug (fP) on tissue binding can be deduced from a plot of fP versus V, but not from a plot of fP versus beta.

Should Medications be Coadministered with Albumin in Hypoalbuminemic Patients

“…It is only the unbound portion of the drug that is pharmacologically active [2]. Thus, medications that are highly protein bound have a lower free fraction; the inverse relationship exists for minimally protein bound drugs.…”

Factors Contributing to Variability in Drug Pharmacokinetics. Ii. Drug Distribution*

“…less than 15 litre) a decrease in plasma protein binding will result in a shortening of half-life. If the initial apparent volume of distribution is greater than 15 litre, the half-life of drugs will alter very little with changes in plasma protein binding (15).…”

Ibuprofen kinetics in patients with renal insufficiency who are receiving maintenance hemodialysis

“…The mean free fraction was 3.08% in the patients, compared with 1.07% in the controls (P < 0.01). The reduced serum protein binding of ibuprofen importantly altered the interpretation of kinetic variables (12)(13)(14)(15)(16)(17). After correction for individual values of protein binding, volume of distribution of unbound ibuprofen was significantly smaller in renal failure patients compared with controls, and peak serum levels of unbound ibuprofen were significantly higher.…”

“…This increase in free fraction in and of itself would not alter the kinetic profile of the pharmacologically active unbound drug, nor would it alter the clinical effect of ibuprofen (12). On the other hand, binding changes have an important influence on the interpretation of pharmacokinetic variables based on lotal (free plus bound) serum levels (12)(13)(14)(15)(16)(17)(18)(19).…”

“…Thus, distribution and clearance are, if anything, reduced in dialysis-dependent patients with renal insufficiency: The opposite conclusions might have been drawn if the serum concentrations of total ibuprofen had been considered alone. This emphasizes the need for correction of kinetic variables for individual values of free fraction during pharmacokinetic studies of disease states which might be associated with altered drug binding to plasma protein (12)(13)(14)(15)(16)(17)(18)(19).…”