Comparison of cerebral Open Flow Microperfusion and Microdialysis when sampling small lipophilic and small hydrophilic substances

Altendorfer‐Kroath, Thomas; Schimek, Denise; Eberl, Anita; Rauter, Günther; Ratzer, Maria; Raml, Reingard; Sinner, Frank; Birngruber, Thomas

doi:10.1016/j.jneumeth.2018.09.024

Cited by 13 publications

(19 citation statements)

References 28 publications

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“…In line with our results, small lipophilic and small hydrophilic substances have been shown to be more efficiently recovered via cOFM in comparison to MD. 21 This opens the possibility of studying brain ISF exposure at treatment-relevant low dose (e.g., i.v. injection of 5 mg/kg; data not shown), and makes it possible to study non-linear PK processes where uptake mechanisms (e.g., transferrin receptors trojan horse approach) can be saturated at high doses.…”

Section: Discussionmentioning

confidence: 99%

Collecting antibodies and large molecule biomarkers in mouse interstitial brain fluid: a comparison of microdialysis and cerebral open flow microperfusion

Prieult

Barini

Laplanche

et al. 2021

mAbs

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The determination of concentrations of large therapeutic molecules, like monoclonal antibodies (mAbs), in the interstitial brain fluid (ISF) is one of the cornerstones for the translation from preclinical species to humans of treatments for neurodegenerative diseases. Microdialysis (MD) and cerebral open flow microperfusion (cOFM) are the only currently available methods for extracting ISF, and their use and characterization for the collection of large molecules in rodents have barely started. For the first time, we compared both methods at a technical and performance level for measuring ISF concentrations of a non-targetbinding mAb, trastuzumab, in awake and freely moving mice. Without correction of the data for recovery, concentrations of samples are over 10-fold higher through cOFM compared to MD. The overall similar pharmacokinetic profile and ISF exposure between MD (corrected for recovery) and cOFM indicate an underestimation of the absolute concentrations calculated with in vitro recovery. In vivo recovery (zeroflow rate method) revealed an increased extraction of trastuzumab at low flow rates and a 6-fold higher absolute concentration at steady state than initially calculated with the in vitro recovery. Technical optimizations have significantly increased the performance of both systems, resulting in the possibility of sampling up to 12 mice simultaneously. Moreover, strict aseptic conditions have played an important role in improving data quality. The standardization of these complex methods makes the unraveling of ISF concentrations attainable for various diseases and modalities, starting in this study with mAbs, but extending further in the future to RNA therapeutics, antibody-drug conjugates, and even cell therapies.

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Section: Discussionmentioning

confidence: 99%

Collecting antibodies and large molecule biomarkers in mouse interstitial brain fluid: a comparison of microdialysis and cerebral open flow microperfusion

Prieult

Barini

Laplanche

et al. 2021

mAbs

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“…The BBB is probably disrupted again after insertion of the sampling insert and flushing with the perfusate as it is in direct contact with the brain tissue (because of the absence of a membrane). Most cOFM studies in the literature are performed under anesthesia, which restricts the duration of the sampling experiment itself and makes a longer run-in phase impossible [ 41 , 43 , 45 , 80 , 83 , 84 ]. In an awake setup, the equilibration period can and should be prolonged [ 25 , 44 ].…”

Section: Strengths and Limitationsmentioning

confidence: 99%

Current Approaches to Monitor Macromolecules Directly from the Cerebral Interstitial Fluid

et al. 2022

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Gaining insights into the pharmacokinetic and pharmacodynamic properties of lead compounds is crucial during drug development processes. When it comes to the treatment of brain diseases, collecting information at the site of action is challenging. There are only a few techniques available that allow for the direct sampling from the cerebral interstitial space. This review concerns the applicability of microdialysis and other approaches, such as cerebral open flow microperfusion and electrochemical biosensors, to monitor macromolecules (neuropeptides, proteins, …) in the brain. Microdialysis and cerebral open flow microperfusion can also be used to locally apply molecules at the same time at the site of sampling. Innovations in the field are discussed, together with the pitfalls. Moreover, the ‘nuts and bolts’ of the techniques and the current research gaps are addressed. The implementation of these techniques could help to improve drug development of brain-targeted drugs.

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“…In contrast, the exchange area of the cOFM probe features macroscopic openings, and thus samples collected by cOFM contain unfiltered cerebral ISF. All compounds, regardless of size (e.g., large molecules like proteins, cytokines, or antibodies) or lipophilicity, can enter the cOFM probe, so the total drug concentration in the ISF (including free and bound fractions) can be assessed from the collected samples (Altendorfer-Kroath et al, 2018). Air bubbles inside push syringe and push tubing before start of sampling Air bubbles may occur during filling.…”

Section: Background Informationmentioning

confidence: 99%

“…Therefore, we conclude that the cOFM sampling procedure did not change the permeability of the BBB and that cOFM sampling is a robust method. This NaFl protocol can be used to assess BBB integrity and to validate cOFM performance (Altendorfer-Kroath et al, 2018;Birngruber et al, 2013;Ghosh et al, 2014).…”

Section: Of 14mentioning

confidence: 99%

“…The perfusate should be a physiological fluid that mimics cerebral ISF. Because the composition of cerebral ISF has not been well characterized, artificial cerebrospinal fluid (CSF) is commonly used (Altendorfer‐Kroath et al., ). The colloid osmotic pressure of the artificial CSF can be adapted to that of cerebral ISF by addition of different proteins.…”

Section: Strategic Planningmentioning

confidence: 99%

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Cerebral Open Flow Microperfusion to Monitor Drug Transport Across the Blood‐Brain Barrier

2019

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Drugs for neurological diseases have to cross the blood‐brain barrier (BBB) to induce their therapeutic effect. In vivo drug quantification in the brain is challenging, because invasive methods damage the BBB and measurement results may be confounded by drug leakage from the blood into the brain through the disrupted BBB. Cerebral open flow microperfusion (cOFM) is an in vivo sampling technique that allows BBB healing and re‐establishment after probe implantation and before sampling is performed. It therefore provides the opportunity to sample compounds in cerebral interstitial fluid with an intact BBB. This article comprehensively describes the experimental setup and procedures, perfusate requirements, critical parameters, common problems that may occur, and their causes and solutions. Typical results from a cOFM sampling experiment are presented and discussed. This protocol provides a tool for performing pharmacokinetic and pharmacodynamic studies in mouse or rat brain with an intact BBB. © 2019 by John Wiley & Sons, Inc.

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Comparison of cerebral Open Flow Microperfusion and Microdialysis when sampling small lipophilic and small hydrophilic substances

Cited by 13 publications

References 28 publications

Collecting antibodies and large molecule biomarkers in mouse interstitial brain fluid: a comparison of microdialysis and cerebral open flow microperfusion

Collecting antibodies and large molecule biomarkers in mouse interstitial brain fluid: a comparison of microdialysis and cerebral open flow microperfusion

Current Approaches to Monitor Macromolecules Directly from the Cerebral Interstitial Fluid

Cerebral Open Flow Microperfusion to Monitor Drug Transport Across the Blood‐Brain Barrier

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