Disease-Induced Variations in Plasma Protein Levels

Abstract

Many diseases appear to lead to a decrease of drug plasma binding due either to hypoalbuminaemia or to a modification of albumin structure. In other diseases, the binding of a drug may increase due to elevated concentrations of alpha 1-acid glycoprotein or lipoproteins. However that may be, the free fraction of a drug may vary in different pathologies. But an increase or decrease of the drug free fraction does not automatically mean an increase or decrease of the free drug concentration. Whatever the drug, a variation in the volume of distribution more or less proportional to the variation in the plasma free fraction can be expected. With respect to the clearance, the problem is much more complex and depends on the hepatic extraction ratio of drug. If the extraction is related to the free fraction (fu) of drug, a variation in fu will lead to a variation in the total drug concentration but no variation in the free drug concentration and no change in the pharmacological effect. If the extraction of a drug is dependent on hepatic flow, a variation in fu will lead to a change in the free drug concentration (with no change in the total drug concentration) and hence changes in the pharmacological effect. The aim of this article is to review the literature concerning disease-induced variations in plasma protein levels during the past 10 years. Finally, possible implications for drug dosage regimens are discussed generally from examples studies in the literature.

Concentration of tacrolimus and major metabolites in kidney transplant recipients as a function of diabetes mellitus and cytochrome P450 3A gene polymorphism

“…Longer tacrolimus T max in the patients with diabetes is most likely due to the delayed gastric emptying. Diabetes alters drug protein binding due to elevated protein glycation (Zini et al ., 1990). Several clinical studies have investigated the effect of diabetes on CYP3A4 activity.…”

“…Despite this, expression and activity of major human phase I and II drug metabolizing enzymes, under diabetes condition, was reported only in a few studies (Cheng et al ., 2001; Dostalek et al ., 2011a; Dostalek et al ., 2011b). These alterations along with other factors such as altered drug absorption, protein binding and distribution (Zini et al 1990, Dostalek et al 2012a) may have a considerable impact on the concentration of tacrolimus and its major metabolites.…”

Nonparametric population modeling of valproate pharmacokinetics in epileptic patients using routine serum monitoring data: implications for dosage

“…If concurrent changes in hepatic metabolism occur, total plasma VAL concentrations can vary depending on the relative magnitude of these mechanisms. In such clinical situations monitoring of free drug concentration may be indicated (6, 18, 37, 38).…”

My affection for Shneior Lifson

“…Fraction bound values obtained using the 96‐well dialysis block and the Spectrum apparatus were very similar to each other and consistent with literature values21–30(Table 1). There were minor shifts in fraction bound values between successive experiments that were attributed to intersubject variations in plasma protein concentrations 31–34. However, the same few drugs (propranolol, ketamine, and imipramine) consistently had a higher percentage of drug bound in the 96‐well block relative to the Spectrum dialyzer.…”