title: Diurnal variation in P-glycoprotein-mediated transport and cerebrospinal fluid turnover in the brain.
abstract: Nearly all bodily processes exhibit circadian rhythmicity. As a consequence, the pharmacokinetic and pharmacodynamic properties of a drug may also vary with time of day. The objective of this study was to investigate diurnal variation in processes that regulate drug concentrations in the brain, focusing on P-glycoprotein (P-gp). This efflux transporter limits the distribution of many drugs in the brain. To this end, the exposure to the P-gp substrate quinidine was determined in the plasma and brain tissue after intravenous administration in rats at six different time points over the 24-h period. Our results indicate that time of administration significantly affects the exposure to quinidine in the brain. Upon inhibition of P-gp, exposure to quinidine in brain tissue is constant over the 24-h period. To gain more insight into processes regulating brain concentrations, we used intracerebral microdialysis to determine the concentration of quinidine in brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) after intravenous administration at two different time points. The data were analyzed by physiologically based pharmacokinetic modeling using NONMEM. The model shows that the variation is due to higher activity of P-gp-mediated transport from the deep brain compartment to the plasma compartment during the active period. Furthermore, the analysis reveals that CSF flux is higher in the resting period compared to the active period. In conclusion, we show that the exposure to a P-gp substrate in the brain depends on time of administration, thereby providing a new strategy for drug targeting to the brain.
authors.affiliation: Division of Pharmacology, LACDR, Leiden University, PO Box 9502, 2300 RA, Leiden, The Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Kervezee
authors.forename: Robin
authors.initials: R
authors.lastname: Hartman
authors.forename: Dirk-Jan
authors.initials: DJ
authors.lastname: van den Berg
authors.forename: Shinji
authors.initials: S
authors.lastname: Shimizu
authors.forename: Yumi
authors.initials: Y
authors.lastname: Emoto-Yamamoto
authors.forename: Johanna H
authors.initials: JH
authors.lastname: Meijer
authors.forename: Elizabeth C M
authors.initials: EC
authors.lastname: de Lange
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D002940:Circadian Rhythm; D004334:Drug Administration Schedule; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D011802:Quinidine / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid*; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011802:Quinidine