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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

Pharmaceutical Research volume 39, pages 251–261 (2022)Cite this article

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.

Author information

Author notes

  1. Ekram Ahmed Chowdhury

    Present address: Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York, 14214, USA

  2. Md Sanaullah Sajib

    Present address: Food and Drug Administration, Silver Spring, Maryland, 20903, USA

  3. Behnam Noorani, Ekram Ahmed Chowdhury and Faleh Alqahtani contributed equally

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S Coulter St., Amarillo, Texas, 79106, USA

    Behnam Noorani, Ekram Ahmed Chowdhury, Faleh Alqahtani, Md Sanaullah Sajib, Yeseul Ahn, Ehsan Nozohouri, Constantinos Mikelis & Ulrich Bickel

  2. Center for Blood-Brain Barrier Research, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, 79106, USA

    Behnam Noorani, Ekram Ahmed Chowdhury, Faleh Alqahtani, Md Sanaullah Sajib, Yeseul Ahn, Ehsan Nozohouri, Constantinos Mikelis, Reza Mehvar & Ulrich Bickel

  3. Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia

    Faleh Alqahtani

  4. LC-MS Core Facility, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, 79106, USA

    Dhavalkumar Patel

  5. Department of Pharmacy, University of Patras, 26504, Patras, Greece

    Constantinos Mikelis

  6. Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Rinker Health Science Campus, 9401 Jeronimo Road, Irvine, California, 92618, USA

    Reza Mehvar

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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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KEY WORDS

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