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A Semi-Physiological Three-Compartment Model Describes Brain Uptake Clearance and Efflux of Sucrose and Mannitol after IV Injection in Awake Mice

Abstract

Purpose

To evaluate a three-compartmental semi-physiological model for analysis of uptake clearance and efflux from brain tissue of the hydrophilic markers sucrose and mannitol, compared to non-compartmental techniques presuming unidirectional uptake.

Methods

Stable isotope-labeled [13C]sucrose and [13C]mannitol (10 mg/kg each) were injected as IV bolus into the tail vein of awake young adult mice. Blood and brain samples were taken after different time intervals up to 8 h. Plasma and brain concentrations were quantified by UPLC-MS/MS. Brain uptake clearance (Kin) was analyzed using either the single-time point analysis, the multiple time point graphical method, or by fitting the parameters of a three-compartmental model that allows for symmetrical exchange across the blood-brain barrier and an additional brain efflux clearance.

Results

The three-compartment model was able to describe the experimental data well, yielding estimates for Kin of sucrose and mannitol of 0.068 ± 0.005 and 0.146 ± 0.020 μl.min−1.g−1, respectively, which were significantly different (p < 0.01). The separate brain efflux clearance had values of 0.693 ± 0.106 (sucrose) and 0.881 ± 0.20 (mannitol) μl.min−1.g−1, which were not statistically different. Kin values obtained by single time point and multiple time point analyses were dependent on the terminal sampling time and showed declining values for later time points.

Conclusions

Using the three-compartment model allows determination of Kin for small molecule hydrophilic markers with low blood-brain barrier permeability. It also provides, for the first time, an estimate of brain efflux after systemic administration of a marker, which likely represents bulk flow clearance from brain tissue.

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Data Availability Statement

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors declare no conflict of interest.

Funding

The present studies were supported by a grant to U.B. from TTUHSC Office of Sciences. F.A. was supported by a stipend from King Saud University, Riyadh, Saudi Arabia.

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Authors and Affiliations

Authors

Contributions

U.B., R.M. and B.N. conceived and designed the study. B.N., E.A.C., F.A., M.S.S., Y.S., E.N. and N.M. conducted the animal experiments. B.N., E.A.C., F.A. and D.P. conducted the LC-MS/MS analysis of the samples. B.N., E.A.C., F.A., U.B. and R.M. performed the PK analysis.

B.N., U.B. and R.M. prepared the manuscript. All authors analyzed and discussed the results and reviewed the manuscript.

Corresponding authors

Correspondence to Reza Mehvar or Ulrich Bickel.

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Noorani, B., Chowdhury, E.A., Alqahtani, F. et al. A Semi-Physiological Three-Compartment Model Describes Brain Uptake Clearance and Efflux of Sucrose and Mannitol after IV Injection in Awake Mice. Pharm Res 39, 251–261 (2022). https://doi.org/10.1007/s11095-022-03175-4

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  • DOI: https://doi.org/10.1007/s11095-022-03175-4

KEY WORDS

  • blood-brain barrier
  • bulk flow
  • LC-MS/MS
  • pharmacokinetics