The influence of diazepam on the serum protein binding of bupivacaine at normal and acidic pH

Abstract

Since both bupivacaine and diazepam are highly protein bound, it is possible that a drug displacement interaction could occur, resulting in an increase in free bupivacaine concentration that could exacerbate systemic toxicity. This study was undertaken to characterize the serum binding of diazepam and to evaluate any drug displacement interaction between diazepam and bupivacaine. Human serum obtained from venous blood of normal male and female volunteers was used for measurements of protein binding using an Amicon Micropartition System. Bupivacaine protein binding in the presence of 0, 0.5 and 1.5 microgram/ml diazepam was best described by the model for two classes of binding sites. Neither concentration of diazepam significantly altered the capacity or affinity for either class of bupivacaine binding sites when compared to control. Free concentrations of bupivacaine were statistically identical in the presence of both diazepam concentrations. The complete diazepam binding profile in both serum and isolated human serum albumin was best described by a model describing two classes of binding sites. The effect of an acidic pH on bupivacaine was also independent of diazepam concentration. Diazepam protein binding was not affected by a reduction in pH from 7.4 to 7.0. The data reported here suggest no binding displacement interaction exists between bupivacaine and concomitantly administered diazepam. Thus, administration of diazepam during a toxic reaction associated with bupivacaine should not alter free bupivacaine concentration.