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. 2022 Aug 24;14(9):1764.
doi: 10.3390/pharmaceutics14091764.

Revisiting Cerebrospinal Fluid Flow Direction and Rate in Physiologically Based Pharmacokinetic Model

Makoto Hirasawa  1 , Elizabeth C M de Lange  1
Affiliations

Revisiting Cerebrospinal Fluid Flow Direction and Rate in Physiologically Based Pharmacokinetic Model

Makoto Hirasawa et al. Pharmaceutics. .

Abstract

The bidirectional pulsatile movement of cerebrospinal fluid (CSF), instead of the traditionally believed unidirectional and constant CSF circulation, has been demonstrated. In the present study, the structure and parameters of the CSF compartments were revisited in our comprehensive and validated central nervous system (CNS)-specific, physiologically based pharmacokinetic (PBPK) model of healthy rats (LeiCNS-PK3.0). The bidirectional and site-dependent CSF movement was incorporated into LeiCNS-PK3.0 to create the new LeiCNS-PK"3.1" model. The physiological CSF movement rates in healthy rats that are unavailable from the literature were estimated by fitting the PK data of sucrose, a CSF flow marker, after intra-CSF administration. The capability of LeiCNS-PK3.1 to describe the PK profiles of other molecules was compared with that of the original LeiCNS-PK3.0 model. LeiCNS-PK3.1 demonstrated superior description of the CSF PK profiles of a range of small molecules after intra-CSF administration over LeiCNS-PK3.0. LeiCNS-PK3.1 also retained the same level of predictability of CSF PK profiles in cisterna magna after intravenous administration. These results support the theory of bidirectional and site-dependent CSF movement across the entire CSF space over unidirectional and constant CSF circulation in healthy rats, pointing out the need to revisit the structures and parameters of CSF compartments in CNS-PBPK models.

Keywords: CSF; CSF physiology; bidirectional pulsatile CSF movement; cerebrospinal fluid; intra-CSF administration; physiologically based pharmacokinetic model.

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Conflict of interest statement

M.H. is an employee of Daiichi-Sankyo Co., Ltd. The other author declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of (A) the original LeiCNS-PK3.0 model and (B) the new LeiCNS-PK3.1 model. Green dashed lines represent new features of the LeiCNS-PK3.1 model. Black syringe icons represent three intra-CSF routes of administration. Barriers abbreviations: BBB—blood–brain barrier; BCSFB—blood–CSF barrier. Compartments abbreviations: CM—cisterna magna; CP—choroid plexus; CSF—cerebrospinal fluid; ECF—extracellular fluid; ICF—intracellular fluid; LV—lateral ventricles; MV—microvessel; SAS—subarachnoid space; TFV—third and fourth ventricles. Factors abbreviations: PHF—pH factor. Flow rates abbreviations: cisQCSF,D—downward cisternal CSF movement rate; cisQCSF,U—upward cisternal CSF movement rate; QCBF—cerebral blood flow rate; QCPBF—CP blood flow rate; QCSF—CSF flow rate; QECF—ECF bulk flow rate; venQCSF,D—downward ventricular CSF movement rate; venQCSF,U—upward ventricular CSF movement rate; Clearance abbreviations: CLcen—central clearance; CLcen-per1/2—distribution clearance between central and peripheral compartments; CLLYSO—transmembrane clearance of lysosomes; CLow—lipid-to-water clearance; CLwo—water-to-lipid clearance; CLp—paracellular transport clearance; CLT,ef—efflux transcellular clearance; CLT,in—influx transcellular clearance; sasQCSF—transfer clearance from SAS to plasma; Administration routes abbreviations: IC—intracisternal; ICV—intracerebroventricular; IT—intrathecal.
Scheme 1
Scheme 1
Overview of work steps in the current study with the original LeiCNS-PK3.0 model and the new LeiCNS-PK“3.1” model. cisQCSF—cisternal CSF flow rate; CSF—cerebrospinal fluid; IV—intravenous.
Figure 2
Figure 2
Parameter sensitivity analysis of cisternal CSF flow rate (cisQCSF) in the unidirectional CSF flow model. (A) Model structure: cisQCSF is highlighted in red. (B) Simulated PK profiles in CM and (C) SAS. Black dots and solid lines represent mean concentrations ± standard error in CM or SAS. Dashed lines represent the median of 200 model simulations changing cisQCSF between 10% (pink) and 60% (purple) of the original QCSF value. BCSFB—blood–CSF barrier; cisQCSF—cisternal CSF flow rate; CM—cisterna magna; CSF—cerebrospinal fluid; LV—lateral ventricles; MV—brain microvessel; QCSF—CSF flow rate; SAS—subarachnoid space; sasQCSF—transfer clearance from SAS to plasma; TFV—third and fourth ventricles; venQCSF—ventricular CSF flow rate.
Figure 3
Figure 3
Comparison of simulated PK profiles of two CSF bulk flow marker molecules with the LeiCNS-PK3.1 model to the observed ones after intra-CSF administration. Dots and solid lines represent mean concentrations ± standard deviation or standard error in CM (khaki), SAS (orange) and plasma (black). Dashed lines represent the median of 200 model simulations with 95% prediction intervals (colored band). (A) [3H]sucrose after ICV administration, (B) [14C]sucrose after IC administration, (C) inulin after ICV administration, and (D) [14C]inulin after IC administration. CM—cisterna magna; CSF—cerebrospinal fluid; IC—intracisternal; ICV—intracerebroventricular; LV—lateral ventricles; SAS—subarachnoid space.
Figure 4
Figure 4
Comparison of simulated PK profiles of eight molecules with the LeiCNS-PK3.1 model to the observed ones after intra-CSF administration. Dots and solid lines represent mean concentrations ± standard deviation or standard error in CM (khaki), SAS (orange), plasma (black) and ECF (red). Dashed lines represent the median of 200 model simulations with 95% prediction intervals (colored band). Red horizontal dashed lines in (C,D) represent the lower limit of quantification of atenolol. (A) morphine-6-glucuronide after ICV administration, (B) morphine after ICV administration, (C,D) atenolol after ICV administration, (E,F) acetaminophen after ICV administration, (G) antipyrine after ICV administration, (H) cefodizime after ICV administration, (I) guanidinosuccinic acid after ICV administration and (J) ziconotide after IT administration. CM—cisterna magna; ECF—brain extracellular fluid; ICV—intracerebroventricular; IT—intrathecal; M6G—morphine-6-glucuronide; SAS—subarachnoid space.
Figure 5
Figure 5
Comparison of PK profiles after IV administration in plasma (left) and CM (middle) simulated with the LeiCNS-PK3.1 model to those in CM (right) simulated with the LeiCNS-PK3.0 model. Dots and solid lines represent mean concentrations ± standard deviation or standard error in CM (khaki) and plasma (black). Dashed lines represent the median of 200 model simulations with 95% prediction intervals (colored band). (A) Atenolol, (B) acetaminophen, (C) antipyrine, (D) cefodizime and (E) ziconotide. CM—cisterna magna.
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