Tissue Physiology of Cynomolgus Monkeys: Cross-Species Comparison and Implications for Translational Pharmacology

• Published in: The AAPS journal Vol. 20; no. 6; p. 107
• Main Authors: Mandikian, Danielle, Figueroa, Isabel, Oldendorp, Amy, Rafidi, Hanine, Ulufatu, Sheila, Schweiger, Michelle G., Couch, Jessica A., Dybdal, Noel, Joseph, Sean B., Prabhu, Saileta, Ferl, Gregory Z., Boswell, C. Andrew
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-11-2018
• Subjects: Biochemistry; Biomedical and Life Sciences; Biomedicine; Biotechnology; Pharmacology/Toxicology; Pharmacy; Research Article; allometric scaling; tissue physiological parameters; translational pharmacology; non-human primates; physiologically based pharmacokinetic modeling
• ISSN: 1550-7416; 1550-7416
• DOI: 10.1208/s12248-018-0264-z

We previously performed a comparative assessment of tissue-level vascular physiological parameters in mice and rats, two of the most commonly utilized species in translational drug development. The present work extends this effort to non-human primates by measuring tissue- and organ-level vascular volumes (
V
v
), interstitial volumes (
V
i
), and blood flow rates (
Q
) in cynomolgus monkeys. These measurements were accomplished by red blood cell labeling, extracellular marker infusion, and rubidium chloride bolus distribution, respectively, the same methods used in previous rodent measurements. In addition, whole-body blood volumes (BV) were determined across species. The results demonstrate that
V
v
,
V
i
, and
Q
, measured using our methods scale approximately by body weight across mouse, rat, and monkey in the tissues considered here, where allometric analysis allowed extrapolation to human parameters. Significant differences were observed between the values determined in this study and those reported in the literature, including
V
v
in muscle, brain, and skin and
Q
in muscle, adipose, heart, thymus, and spleen. The impact of these differences for selected tissues was evaluated via sensitivity analysis using a physiologically based pharmacokinetic model. The blood-brain barrier in monkeys was shown to be more impervious to an infused radioactive tracer, indium-111-pentetate, than in mice or rats. The body weight-normalized total BV measured in monkey agreed well with previously measured value in rats but was lower than that in mice. These findings have important implications for the common practice of scaling physiological parameters from rodents to primates in translational pharmacology.