Effect of blood sampling schedules on protein drug binding in the rat.
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 Blood samples were withdrawn at pre-determined intervals and hematocrit, total plasma protein, plasma albumin and free fatty acids were measured.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.
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D001800:Blood Specimen Collection / Q000379:methods / Q000662:veterinary*; D001728:Dicumarol / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006400:Hematocrit / Q000662:veterinary; D008297:Male; D004364:Pharmaceutical Preparations / Q000097:blood*; D011485:Protein Binding; D051381:Rats / Q000097:blood*; D013997:Time Factors
D001798:Blood Proteins; D005230:Fatty Acids, Nonesterified; D004364:Pharmaceutical Preparations; D001728:Dicumarol