Rate of small-molecular drug transport across the blood-brain barrier in a pericyte-deficient state.

Close interactions between pericytes and brain endothelial cells are essential for keeping the blood-brain barrier (BBB) functional and to restrict the transport of various xenobiotics from blood circulation to the brain parenchyma. Profound understanding of pericyte roles at the BBB and underlying mechanisms for the regulation of BBB transport are important as a potential strategy to improve drug delivery in treatment of CNS disorders. The aim of the present study was to investigate pericyte role in the rate of small-molecular drug transport across the BBB, by examining three model compounds in a pericyte-deficient state. Diazepam, oxycodone and paliperidone were selected for this purpose based on utilization of different transport mechanisms at the BBB. The rate of brain uptake was assessed by implementing the trans-cardiac in situ brain perfusion technique. Radiolabeled 14C-sucrose was used as a vascular marker. Pericyte-deficient mice (Pdgfbret/ret) exhibited significantly larger brain vascular volumes (Vvasc) 1.72 ±â€¯0.13 mL/100 g brain, compared to littermate controls with normal pericyte coverage (Pdgfbret/+) 1.15 ±â€¯0.13 mL/100 g brain (p < 0001). However, the unidirectional transfer coefficient Kin, which describes the rate of brain uptake, was not different between Pdgfbret/ret and Pdgfbret/+ mice for all three tested compounds. Taken together the present results indicate no pericyte influence in the rate of small-molecular drug transport at the BBB, despite the larger brain vascular volumes that were observed in a pericyte-deficient state.

Pharmacokinetics of pericyte involvement in small-molecular drug transport across the blood-brain barrier.

Pericytes are perivascular cells that play important roles in the regulation of the blood-brain barrier (BBB) properties. Pericyte-deficiency causes compromised BBB integrity and increase in permeability to different macromolecules mainly by upregulated transcytosis. The aim of the present study was to investigate pericyte involvement in the extent of small-molecular drug transport across the BBB. This was performed with five compounds: diazepam, digoxin, levofloxacin, oxycodone and paliperidone. Compounds were administered at low doses via subcutaneous injections as a cassette (simultaneously) to pericyte-deficient Pdgfbret/ret mice and corresponding WT controls. Total drug partitioning across the BBB was calculated as the ratio of total drug exposures in brain tissue and plasma (Kp,brain). In addition, equilibrium dialysis experiments were performed to estimate unbound drug fractions in brain (fu,brain) and plasma (fu,plasma). This enabled estimation of unbound drug partitioning coefficients (Kp,uu,brain). The results indicated slight tendencies towards increase of total brain exposures in Pdgfbret/ret mice as reflected in Kp,brain values, which were within the 2-fold limit. Part of these differences could be explained by differences in plasma protein binding. No difference was found in brain tissue binding. The combined in vivo and in vitro data resulted in no differences in BBB transport in pericyte-deficiency, as described by similar Kp,uu,brain values in Pdgfbret/ret and control mice. In conclusion, these findings imply no influence of pericytes on the extent of BBB transport of small-molecular drugs, and suggest preserved BBB features relevant for handling of this type of molecules irrespective of pericyte presence at the brain endothelium.