Plasma proteins altered drug binding

Some AEDs, especially phenytoin and valproate, are highly bound to plasma proteins. When interpreting a reported concentration for these drugs, it is important to remember that the value represents the total (i.e., bound and unbound) concentration in the blood. Because of differences in the metabolism of these drugs, the clinical effects of altered protein binding are different for different drugs. 

Drug distribution in elderly patients may be altered by hypoalbuminemia, qualitative changes in drug-binding sites, reductions in relative muscle mass, increases in the proportion of body fat, and decreases in total body water. The plasma level of free, active drug is often a direct function of the extent of drug binding to plasma proteins. There is a well-documented age-dependent decline (about 20%) in plasma albumin concentration in humans due to a reduced rate of hepatic albumin... 

Carbamazepine is widely distributed in the cerebros-piral fluid (CSF), bile, and saliva (AHFS, 2000). Plasma concentrations for anticonvulsant effect are in the range of 4-14 pg/mL. Carbamazepine, like DVP, is highly bound to protein (over 90%). At plasma concentrations of 1-50 pg/mL, 75%-90% of the drug is bound to plasma proteins (Trimble and Thompson, 1984). When protein-binding capacity is altered, marked changes in the free fractions can happen. Carbamazepine rapidly crosses the placenta, accumulates in fetal tissues, and is distributed in breast milk (AHFS, 2000). 

Gabapentin does not bind to plasma proteins, is not appreciably metabolized, nor induces hepatic enzyme activity (AHFS, 2000) Consequently, it does not appear to alter the pharmacokinetics of commonly used anticonvulsant drugs or oral contraceptives (Ketter et al.,... 

The mechanisms by which drug interactions alter drug distribution include (1) competition for plasma protein binding,... 

One of the most important practical aspects of protein binding is the fact that drugs of similar or markedly dissimilar structure may compete for the same binding sites on the protein (7). Hence, multidrug therapy may lead to alteration in the plasma concentration and the rate of elimination of drugs, because of multiple competition for the plasma protein-binding sites. 

The nutritional status of an animal may affect the disposition of a foreign compound in vivo as well as the metabolism. Many drugs are protein-bound in the plasma, and alteration of the extent of binding for compounds extensively bound may have important toxicological implications. Thus, the decreased plasma levels of albumin after low-protein diets, such as occur in the human deficiency disease Kwashiorkor, might lead to significantly increased plasma levels of the free drug and therefore the possibility of increased toxicity. 

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