Serum protein binding kinetics of phenytoin in monotherapy patients

Abstract

Our results suggest that there may be small differences in the binding characteristics of phenytoin to serum proteins between Japanese and non-Japanese subjects. The unbound serum fraction of phenytoin in our patients with epilepsy can be assumed to be relatively constant in the therapeutic concentration range of phenytoin.

Analysis of Free Drug Fractions Using Near-Infrared Fluorescent Labels and an Ultrafast Immunoextraction/Displacement Assay

“…This drug is mainly bound in blood to the protein human serum albumin (HSA), with approximately 90% of phenytoin being complexed at therapeutic levels in adults [8][9][10][11][12][13][14]. Two clinical situations in which the bound fraction of phenytoin might decrease include infants with jaundice (due to the competition of bilirubin with phenytoin for HSA) and patients that have low HSA levels following trauma or surgery [9].…”

Studies by biointeraction chromatography of binding by phenytoin metabolites to human serum albumin

“…It has non-linear dose-dependent pharmacokinetics and is mostly excreted in bile as inactive metabolites, which are then reabsorbed from the intestinal tract and excreted in urine [3,4]. The primary metabolites of phenytoin are 5-(3-hydroxyphenyl)-5-phenylhydantoin (m-HPPH) and 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) (see Figure 1) [4].…”

“…When phenytoin is present in blood, it is highly bound to the carrier protein human serum albumin (HSA) [3,7]. A few reports have indicated that phenytoin interacts at the warfarinazapropazone site of HSA [8,9], while others have noted competition between phenytoin and digitoxin through the digitoxin site on HSA [10].…”

Studies of phenytoin binding to human serum albumin by high-performance affinity chromatography

“…Most of this binding occurs with HSA [11], but a small fraction also binds to ␣-globulins [12,13] and ␤-lipoproteins [14]. The results of earlier studies that have examined the interactions of phenytoin with HSA are summarized in Table 1 [11,[15][16][17][18][19]. The association constants reported for phenytoin in such studies have ranged from 745 to 2 × 10 4 M −1 and the number of observed binding sites for this drug on HSA have ranged from 0.85 to 8.…”