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Handb Exp Pharmacol. 2017 Jul 26. doi: 10.1007/164_2017_37. [Epub ahead of print]

Metabolite Clearance During Wakefulness and Sleep.

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Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK.
Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK.


Mechanisms for elimination of metabolites from ISF include metabolism, blood-brain barrier transport and non-selective, perivascular efflux, this last being assessed by measuring the clearance of markers like inulin. Clearance describes elimination. Clearance of a metabolite generated within the brain is determined as its elimination rate divided by its concentration in interstitial fluid (ISF). However, the more frequently measured parameter is the rate constant for elimination determined as elimination rate divided by amount present, which thus depends on both the elimination processes and the distribution of the metabolite in the brain. The relative importance of the various elimination mechanisms depends on the particular metabolite. Little is known about the effects of sleep on clearance via metabolism or blood-brain barrier transport, but studies with inulin in mice comparing perivascular effluxes during sleep and wakefulness reveal a 4.2-fold increase in clearance. Amongst the important brain metabolites considered, CO2 is eliminated so rapidly across the blood-brain barrier that clearance is blood flow limited and elimination quickly balances production. Glutamate is removed from ISF primarily by uptake into astrocytes and conversion to glutamine, but also by transport across the blood-brain barrier. Both lactate and amyloid-β are eliminated by metabolism, blood-brain barrier transport and perivascular efflux and both show decreased production, decreased ISF concentration and increased perivascular clearance during sleep. Taken altogether available data indicate that sleep increases perivascular and non-perivascular clearances for amyloid-β which reduces its concentration and may have long-term consequences for the formation of plaques and cerebral arterial deposits.


Amyloid-beta; Blood—brain barrier transport; Brain interstitial fluid volume; Carbon dioxide; Cerebrospinal fluid; Clearance; Glutamate; Glymphatic circulation; Inulin; Lactate; Metabolite elimination mechanisms; Perivascular efflux; Perivascular spaces; Rate constant for elimination; Volume of distribution


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