Our study aimed at evaluating the cerebral bioavailability of Cladribine across the two major blood-brain interfaces, and deciphering the contribution of transport systems and the influence of metabolism.

Cladribine has a marked effect on the incidence and severity of relapses in multiple sclerosis. The mechanism of this central effect is unclear. Cladribine concentrations in CSF can represent up to 25% of plasma level, but the extent to which the drug penetrates into the CNS via the blood-brain barrier and/or via the blood-CSF barrier (choroid plexus) is unknown. Cladribine is an adenosine analog prodrug. The active drug concentration depends on the ratio between phosphorylation by deoxycytidine kinase and dephosphorylation by ectonucleotidases. Whether phosphorylation occurs en passage through the blood-brain interfaces is unknown.

Phosphorylation of cladribine in intact brain barrier tissues was below detectable level. Cladribine exerted no deleterious effect on the passive permeability of both barrier cell monolayers to the small polar paracellular marker sucrose after short-term or prolonged exposure. A transcellular influx of cladribine mediated by saturable transport systems occured across both barriers. Cladribine was also transported from brain and CSF to blood via saturable systems. The efllux was more active than the influx, which should limit cladribine cerebral penetration . The contribution of different families of influx and efflux transport systems (ABC and SLC28/29 families) was characterized using various specific inhibitors.

Cladribine is transported unmetabolized across blood-brain interfaces by saturable mechanisms. Transport is more efficient at the blood-CSF barrier through which Cladribine gets a direct access to inflammatory cells in CSF and connected subarachnoid spaces.