Determinants of the plasma protein binding of theophylline in health.

Abstract

1 The plasma protein binding of theophylline was determined after addition of ['4C]-theophylline (15 ,g/ml) to plasma from 24 healthy drug-free volunteers and equilibrium dialysis for 2 h at 37°C. 2 The percentage of drug unbound was 60.0% 2.2% (s.d.) with very little variation between individuals. The binding ratio of theophylline was not significantly related to the plasma albumin or a,-acid glycoprotein (AAG) concentrations but was significantly, although weakly, negatively related to the logarithm of the non-esterified fatty acid concentration (NEFA) (r = 0.443, P < 0.05). 3 Intravenous administration of heparin (1000 units) caused a significant rise in plasma NEFA concentration and in the percentage of drug unbound in plasma after equilibrium dialysis. 4 In human serum albumin solutions, the binding ratio of theophylline was significantly related to the albumin concentration and at the albumin concentration seen in the 24 normal subjects, the percentage of drug unbound was almost identical. Addition of AAG in physiological concentrations did not enhance theophylline binding but oleic acid, and to a lesser extent palmitic acid, reduced binding significantly. 5 The percentage of theophylline unbound in plasma varied markedly with pH so that at pH7 the percentage unbound was 52% greater than at pH 8. There was no evidence of concentration dependence of binding up to 140 ,ug/ml theophylline.6 Theophylline appears to bind almost exclusively to albumin and its plasma protein binding varies little in healthy subjects, showing no concentration-dependence over the therapeutic range of concentrations. The binding is affected by pH and by NEFA concentration, however, and these factors may be of greater importance in disease states. Caution should be employed in the use of heparin in studies of plasma protein binding of theophylline.

Protein binding of theophylline.

“…Their finding of concentration-dependent protein binding of theophylline between 5-20 mg/l is, however, at variance with our observations (Buss et al, 1983). Other authors have also suggested that theophylline protein binding could fall with increasing drug concentration.…”

“…Both of these studies used equilibrium dialysis to measure free fraction of theophylline under conditions of controlled temperature (37°C) and pH (7.4) which was not the case with some of the original studies of theophylline plasma protein binding (Buss et al, 1983).…”

Do saliva concentrations predict plasma unbound theophylline concentrations? A problem re‐examined.

“…The mean plasma protein binding in these patients of 58.2 + 5.09%, is similar in males (57.7 + 5.06%) and females (58.8 + 5.1%). These findings are consistent with those of other authors using ultrafiltration (Antal et al, 1981;Aslaksen et al, 1981;Yurchak & Jusko, 1976;Piafsky etal., 1980;Mangione etal., 1978) but somewhat higher than those obtained by equilibrium dialysis at 37°C (Buss et al, 1983;Brors et al, 1983) showing that theophylline binding is temperature dependent, as well as pH dependent (Vallner et al, 1979). There also appears to be a very weak correlation between age and free fraction (r = 0.411) such that theophylline plasma protein binding decreases with advancing years, as reported for other drugs (Wallace et al, 1976;Patterson et al, 1982).…”

Examining Small Intestinal Transit Time as a Function of Age: Is There Evidence to Support Age-Dependent Differences among Children?

“…Tissue:plasma partition coefficients were estimated using in silico tissue composition-based algorithms published by Rodgers et al (2005a,b) and Rodgers and Rowland (2006). Albumin was denoted as the principle binding protein of theophylline in plasma with an average fraction unbound of approximately 0.58 in healthy adults (Buss et al, 1983;Leopold et al, 1985). Human intestinal permeability was estimated for theophylline by scaling from in vitro Caco-2 data (Parrott et al, 2009).…”