Merck
  • Home
  • Search Results
  • Diurnal variation in P-glycoprotein-mediated transport and cerebrospinal fluid turnover in the brain.

Diurnal variation in P-glycoprotein-mediated transport and cerebrospinal fluid turnover in the brain.

The AAPS journal (2014-06-12)
Laura Kervezee, Robin Hartman, Dirk-Jan van den Berg, Shinji Shimizu, Yumi Emoto-Yamamoto, Johanna H Meijer, Elizabeth C M de Lange
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
3-Ethyl-2,4-pentanedione, mixture of tautomers, 98%
Sigma-Aldrich
Triethylamine, for amino acid analysis, ≥99.5% (GC)
Sigma-Aldrich
Triethylamine, BioUltra, ≥99.5% (GC)
Sigma-Aldrich
Triethylamine, puriss. p.a., ≥99.5% (GC)
Sigma-Aldrich
Triethylamine, for protein sequence analysis, ampule, ≥99.5% (GC)
Sigma-Aldrich
Sodium hydroxide solution, BioUltra, for molecular biology, 10 M in H2O
Supelco
Sodium hydroxide solution, 49-51% in water, eluent for IC
Sigma-Aldrich
Sodium hydroxide, BioUltra, for luminescence, ≥98.0% (T), pellets
Sigma-Aldrich
Triethylamine, purum, ≥99% (GC)
Sigma-Aldrich
Triethylamine, ≥99.5%
Sigma-Aldrich
Triethylamine, ≥99%
Sigma-Aldrich
Quinidine sulfate salt dihydrate
Sigma-Aldrich
Sodium hydroxide solution, 1.0 N, BioReagent, suitable for cell culture
Supelco
Sodium hydroxide concentrate, 0.1 M NaOH in water (0.1N), Eluent concentrate for IC
Sigma-Aldrich
Phosphoric acid solution, 85 wt. % in H2O, FCC, FG
Sigma-Aldrich
Boric acid-11B, ≥99 atom % 11B
Supelco
Triethylamine, analytical standard
Sigma-Aldrich
Sodium hydroxide, ultra dry, powder or crystals, 99.99% trace metals basis
Sigma-Aldrich
Phosphoric acid solution, NMR reference standard, 85% in D2O (99.9 atom % D), NMR tube size 3 mm × 8 in.
Sigma-Aldrich
Phosphoric acid solution, NMR reference standard, 85% in D2O (99.9 atom % D), NMR tube size 5 mm × 8 in.
Sigma-Aldrich
Phosphoric acid solution, NMR reference standard, 85% in D2O (99.9 atom % D), NMR tube size 4.2 mm × 8 in. , WGS-5BL Coaxial NMR tube
Sigma-Aldrich
Triethylamine, ≥99.5%
Isoflurane, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Sodium hydroxide, BioXtra, ≥98% (acidimetric), pellets (anhydrous)
Sigma-Aldrich
Sodium hydroxide, puriss., meets analytical specification of Ph. Eur., BP, NF, E524, 98-100.5%, pellets
Sigma-Aldrich
Sodium hydroxide solution, purum, ≥32%
Sigma-Aldrich
Sodium hydroxide, puriss. p.a., ACS reagent, reag. Ph. Eur., K ≤0.02%, ≥98%, pellets
Sigma-Aldrich
Sodium hydroxide, puriss. p.a., ACS reagent, K ≤0.02%, ≥98.0% (T), pellets
Sigma-Aldrich
Sodium hydroxide, reagent grade, 97%, powder
Sigma-Aldrich
Sodium hydroxide, reagent grade, ≥98%, pellets (anhydrous)