P-glycoprotein Function in the Rodent Brain Displays a Daily Rhythm, a Quantitative In Vivo PET Study.
The blood-brain barrier (BBB) contributes to brain homeostasis by protecting the brain from harmful compounds. P-glycoprotein (P-gp) is one of the major efflux transporters at the BBB. In the present study, we assessed whether (1) P-gp function in the brain is constant or fluctuates across the day and (2) if it is affected by sleep deprivation. Four groups of rats were PET scanned with a radiolabeled P-gp substrate [18F]MC225, each at a different moment of the 12-h light-dark cycle to study diurnal variations: early sleep phase (ZT3), late sleep phase (ZT9), early active phase (ZT15), and late active phase (ZT21). In two additional groups, controls were allowed to sleep normally while experimental animals were sleep-deprived for 10 h in a slowly rotating drum during the sleep phase. Kinetic modeling with a one-tissue compartment model fit resulted for all brain regions in 1.2-1.8-fold higher distribution volumes (VT) at ZT15 than at other time points. VT-values at ZT3, ZT9, and ZT21 were not significantly different from each other. Regional tracer distribution volumes in controls and sleep-deprived animals were also not significantly different. Our results indicate that P-gp function in rats displays a daily rhythm with reduced function at the beginning of the active phase. This rhythm is not dependent on sleep since acute sleep deprivation had no effect. Knowing the diurnal variation of P-gp function could be important for the design of PET studies and for choosing the correct administration time for P-gp-dependent drugs.
Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, Netherlands.
Heli
H
Savolainen
Groningen Institute for Evolutionary Life Sciences, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, Netherlands.
Peter
P
Meerlo
Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, Netherlands.
Philip H
PH
Elsinga
Department of Radiology and Nuclear Medicine, VU University Medical Center Amsterdam, De Boelelaan 1085 C, 1081 HV, Amsterdam, Netherlands.
Albert D
AD
Windhorst
Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, Netherlands.
Rudi A J O
RA
Dierckx
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, via Orabona 4, 70125, Bari, Italy.|Biofordrug slr, via Orabona 4, 70125, Bari, Italy.
Nicola A
NA
Colabufo
Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, Netherlands.
Aren
A
van Waarde
Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, Netherlands. g.luurtsema@umcg.nl.
Gert
G
Luurtsema
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D019540:Area Under Curve; D001812:Blood-Brain Barrier; D001921:Brain / Q000502:physiology*; D002940:Circadian Rhythm; D008297:Male; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012892:Sleep Deprivation; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019275:Radiopharmaceuticals
[18F]MC225; circadian rhythm; efflux transporter; pharmacokinetic modeling; sleep deprivation