Effects of obesity and ancillary variables (dialysis time, drug, albumin, and fatty acid concentrations) on theophylline serum protein binding

Abstract

The effect of obesity on the serum protein binding of theophylline was investigated in man and rat along with other ancillary variables such as dialysis time, theophylline concentration, albumin concentration, and fatty acid type and concentration. The percent binding of theophylline first increased with dialysis time, reached equilibrium over 2 to 6 h, then diminished. This decrease was not due to instability of theophylline. Theophylline binding was linear over a concentration range of 15 to 150 micrograms ml-1. A similar degree of binding was found in normal humans (44.4 +/- 1.0%) and rats (41.5 +/- 0.5%). The binding ratio (bound/free) of theophylline was proportional to the albumin concentration (1 to 5%) and yielded a binding parameter (NK) of 1.47 x 10(-3) M-1. Over a normal physiological range, individual and mixed fatty acids had minimal effects on theophylline binding to albumin. However, binding significantly decreased as fatty acid (FFA) concentrations increased. The magnitude of the effect appeared to parallel the carbon chain number of the fatty acid. Theophylline binding in obese subjects decreased to a mean (SD) of 35.8 +/- 8.0 per cent compared to 43.0 +/- 6.1 per cent in normal subjects (p less than 0.05). Similar decreases were found in normal versus obese rats and in the saliva: serum ratio following theophylline administration to normal and obese human subjects. Obesity causes a moderate decrease in serum binding of theophylline which may be attributed to increased FFA rather than in vitro artifacts.

Use of a Physiologically Based Pharmacokinetic Model to Study the Time to Reach Brain Equilibrium: An Experimental Analysis of the Role of Blood-Brain Barrier Permeability, Plasma Protein Binding, and Brain Tissue Binding

“…The unbound fractions in rat plasma (f u,plasma ) and brain homogenate (f u,brain ) measured by an equilibrium dialysis method are also presented in Table 1. The determined unbound fraction in rat plasma is consistent with the values reported in the literature (Bonati et al, 1984;Chauvelot-Moachon et al, 1988;Yasuhara and Levy, 1988;Shum and Jusko, 1989;Caccia et al, 1990). We observed an inverse relationship between permeability and the nonspecific binding in brain homogenate for some of the model compounds.…”

Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling: theophylline and midazolam as model drugs

“…Plasma protein binding of theophylline and midazolam in the infants and children were calculated from the age‐related change in serum albumin concentration [35]. For theophylline, an unbound fraction ( f u ) of 0.56 was assumed for adults [36]. A blood : plasma concentration ratio (λ) of 0.82 has been determined [37].…”

Pharmacokinetic changes of drugs in a rat model of liver cirrhosis induced by dimethylnitrosamine, alone and in combination with diabetes mellitus induced by streptozotocin

“…This suggests that theophylline could be actively reabsorbed for both groups of rats. Plasma protein binding values of theophylline to human serum remain constant, 44.4%, at theophylline concentrations ranging from 15 to 150 µg/ml .…”