Abstract
The effect of repetitive blood sampling schedules on the plasma protein binding of a highly protein-bound drug, dicumarol, was investigated in the rat. Blood samples were withdrawn at pre-determined intervals and hematocrit, total plasma protein, plasma albumin and free fatty acids were measured. Plasma protein binding of [14C]dicumarol was assessed by equilibrium dialysis. Withdrawal of 1 ml of blood every hour for 12 hr produced a significant decrease at 2 hr in hematocrit (42%), total plasma protein (14.5%), plasma albumin (31.4%) and an increase in free fatty acids (238%) compared to the control (O time) levels. The free fraction of dicumarol in the plasma increased 1350%, from 0.38 to 5.13%. Sampling schedules involving blood withdrawal of 0.5 mg/2 hr and 1 ml/2 hr producing less dramatic changes, but in all cases the free fraction of dicumarol was elevated at the 12-hr time period. An inverse relationship was found between plasma albumin concentrations and dicumarol-free fraction. The blood sampling schedule was found to alter the pharmacological response (prothrombin time) and pharmacokinetics of dicumarol after an 8 mg/kg i.v. dose. These results illustrate the influence multiple blood sampling can exert on pharmacodynamic parameters in studies involving small laboratory animals and highly protein-bound drugs.
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|