Whole blood or plasma: what is the ideal matrix for pharmacokinetic-driven drug candidate selection?

In the present era of drug development, quantification of drug concentrations following pharmacokinetic studies has preferentially been performed using plasma as a matrix rather than whole blood. However, it is critical to realize the difference between measuring drug concentrations in blood versus plasma and the consequences thereof. Pharmacokinetics using plasma data may be misleading if concentrations differ between plasma and red blood cells (RBCs) because of differential binding in blood. In this review, factors modulating the partitioning of drugs into RBCs are discussed and the importance of determining RBC uptake of drugs for drug candidate selection is explored. In summary, the choice of matrix (plasma vs whole blood) is an important consideration to be factored in during drug discovery.

Metabolism and toxicity studies supporting the safety of rebaudioside D.

Rebaudioside D (Reb D) is one of the several glycosides found in the leaves of Stevia rebaudiana (Bertoni) Bertoni (Compositae) which has been identified as a potential sweetener. The metabolism of Reb A and Reb D was evaluated in various in vitro matrices (simulated gastrointestinal fluids, rat liver microsomes, and rat cecal contents) and through analysis of plasma collected from rats in a dietary toxicity study. Reb A and Reb D showed similar stability when exposed to simulated stomach and small intestine fluids, with susceptibility to hydrolytic degradation by enteric bacteria collected from the cecum. Incubations with rat liver microsomes indicated that neither compound is expected to be metabolized by the liver enzymes. Plasma concentrations of Reb D, Reb A, and/or the final hydrolysis product of each compound, free/conjugated steviol, were consistent between animals administered either Reb D or Reb A in the diet. A repeated exposure dietary toxicity study was conducted to compare the safety of Reb D, when administered at target exposure levels of 500, 1000, and 2000 mg/kg body weight (bw)/d to Sprague-Dawley rats for 28 days, to that of Reb A administered at a target exposure level of 2000 mg/kg bw/d. There were no treatment-related effects on the general condition and behavior of the animals and no toxicologically relevant, treatment-related effects on hematology, serum chemistry, or urinalysis. Macroscopic and microscopic findings revealed no treatment-related effects on any organ evaluated. Results were comparable between the group administered 2000 mg/kg/d Reb D and the group administered 2000 mg/kg/d Reb A.