Plasma protein binding of theophylline during development in the rabbit

The plasma protein binding profile of theophylline was investigated in the rabbit during the perinatal and developmental period. The roles of unbound plasma theophylline fraction (THu), albumin, nonesterified fatty acids (NEFA) and plasma bilirubin levels were analyzed. Plasma total protein and albumin levels doubled with age from the 1st day of life to maturity (from 3.1 to 5.3 and 1.6 to 3.7 g/l, respectively). THu, NEFA and bilirubin levels were inversely related to age, and decreased from 81 to 37%, 2,136 to 239 microEq/l and 2.4 to 0.20 mg/dl, respectively. A linear correlation was shown between THu and albumin, NEFA, and bilirubin plasma concentrations. Stepwise multiple linear regression analysis, including albumin, NEFA and bilirubin values as independent variables, identified NEFA as the variable explaining most of the variability in plasma protein binding of theophylline. Findings support the need for careful interpretation (with a view to therapeutic utilization) of estimates of plasma protein unbound fraction of a drug during development. This fact highlights the importance of considering not only protein but NEFA concentrations too.