Comparative Physiology of Mice and Rats: Radiometric Measurement of Vascular Parameters in Rodent Tissues

Abstract

A solid understanding of physiology is beneficial in optimizing drug delivery and in the development of clinically predictive models of drug disposition kinetics. Although an abundance of data exists in the literature, it is often confounded by the use of various experimental methods and a lack of consensus in values from different sources. To help address this deficiency, we sought to directly compare three important vascular parameters at the tissue level using the same experimental approach in both mice and rats. Interstitial volume, vascular volume, and blood flow were radiometrically measured in selected harvested tissues of both species by extracellular marker infusion, red blood cell labeling, and rubidium chloride bolus distribution, respectively. The latter two parameters were further compared by whole-body autoradiographic imaging. An overall good interspecies agreement was observed for interstitial volume and blood flow on a weight-normalized basis in most tissues. In contrast, the measured vascular volumes of most rat tissues were higher than for mouse. Mice and rats, the two most commonly utilized rodent species in translational drug development, should not be considered as interchangeable in terms of vascular volume per gram of tissue. This will be particularly critical in biodistribution studies of drugs, as the amount of drug in the residual blood of tissues is often not negligible, especially for biologic drugs (e.g., antibodies) having long circulation half-lives. Physiologically based models of drug pharmacokinetics and/or pharmacodynamics also rely on accurate knowledge of biological parameters in tissues. For tissue parameters with poor interspecies agreement, the significance and possible drivers are discussed.

Interstitial IgG antibody pharmacokinetics assessed by combined in vivo‐ and physiologically‐based pharmacokinetic modelling approaches

“…The residual plasma fractions based on HSA distribution were systematically higher than reported previously (Garg, ; Boswell et al . ). These previous values are based on the distribution of red blood cells.…”

“…, where there is the comparison of the PK profiles for the analysed tissues, including residual plasma corrections based on red blood cell distribution (Garg, ; Boswell et al . ) and based on 125 I‐HSA and 125 anti‐IL‐17 IgG distribution after 5 and 10 min of circulation time, respectively. Hence, a direct assessment of the plasma space is, in our opinion, more representative, with the exception of organs with discontinuous capillaries, where the tracer will quickly extravasate and equilibrate in the entire extravascular phase as discussed earlier.…”

“…; Boswell et al . ), especially considering the different properties of the applied tracers. These findings show that corrective factors have a major impact on estimated extravascular concentration, thus demonstrating the significance of measurements that are exact as possible, as well as careful interpretation of the results.…”

Production, characterization, andin vivohalf-life extension of polymeric IgA molecules in mice

“…Therefore, intact antibody distribution data were blood corrected as previously described to represent only interstitial concentrations in tissues. 42 We observed slight enrichment of intact IgA oligomers compared to IgG1 after 1 h in the liver, stomach, small intestine, large intestine, and skin (all pIgR-expressing tissues 43,44 ), albeit at low levels ( Figure 5B). We also saw high levels of IgA degradation in the liver and small intestine, across the formats studied after 1 h of dosing ( Figure 5C).…”

Influence of molecular size on tissue distribution of antibody fragments

“…11 Further, it might be more appropriate to derive the interstitial concentrations of proteins based on the BC values by employing the respective volumes of vascular and interstitial compartments. 12 It is also important to note that the tissue concentrations derived based on the BC values are valid only for non-target expressing tissues, and does not take into account the target-mediated drug disposition (TMDD) of proteins in target expressing tissues. Based on the expression profile and internalization levels of a target in a given tissue, the TMDD effect can lead to higher or lower interstitial concentrations of a protein than the one predicted using a BC value.…”