Flow Rate and Apparent Volume of Cerebrospinal Fluid in Rhesus Macaques (Macaca mulatta) Based on the Pharmacokinetics of Intrathecally Administered Inulin.

Cerebrospinal fluid (CSF) flow rate and volume are fundamental to the design and interpretation of preclinical pharmacokinetics and pharmacodynamics studies in NHP. To determine the values of CSF flow rate and volume, we evaluated the plasma and CSF pharmacokinetics of inulin, an inert polysaccharide tracer, in 5 rhesus macaques with CSF ventricular res- ervoirs and lumbar ports; these reservoirs and ports facilitate humane intrathecal administration and serial CSF sampling in unanesthetized macaques. Inulin was administered intrathecally via the CSF ventricular reservoir (n = 3), followed by the collection of lumbar CSF via the lumbar port and plasma. The contribution of dietary inulin was evaluated by using pre- and postprandial inulin plasma concentrations (n = 2) and a feed analysis of the NHP diet. Inulin concentrations were quantified using ELISA. Pharmacokinetic parameters were calculated by using noncompartmental methods. Daily diet was analyzed for inulin by using Official Method no. 997.08 of AOAC International. In male rhesus macaques, the mean CSF flow rate, established via inulin clearance after IT administration, was 0.018 ± 0.003 mL/min; mean CSF volume, established based on apparent volume of distribution, was 10.17 ± 0.63 mL. In plasma, inulin was quantifiable in all pre-administration samples and increased over the sampling period, precluding interpretation of plasma pharmacokinetics. Evaluation of the effect of diet on plasma concentrations established quantifiable inulin levels that showed minimal variation relative to the prandial state. Analysis of the feed detected 5 inulin types ranging from 1100 to 1440 mg per100 g. The diet was the source of detectable pre-administration inulin plasma concentrations, whereas inulin was not detected in CSF before inulin administration.

Open- and closed-formula laboratory animal diets and their importance to research.

Almost 40 y ago the scientific community was taking actions to control environmental factors that contribute to variation in the responses of laboratory animals to scientific manipulation. Laboratory animal diet was recognized as an important variable. During the 1970s, the American Institute of Nutrition, National Academy of Science, Institute of Laboratory Animal Resources, and Laboratory Animals Centre Diets Advisory Committee supported the use of 'standard reference diets' in biomedical research as a means to improve the ability to replicate research. As a result the AIN76 purified diet was formulated. During this same time, the laboratory animal nutritionist at the NIH was formulating open-formula, natural-ingredient diets to meet the need for standardized laboratory animal diets. Since the development of open-formula diets, fixed-formula and constant-nutrient-concentration closed-formula laboratory animal natural ingredient diets have been introduced to help reduce the potential variation diet can cause in research.