Hydrophilic drugs, or neuroactive agents characterized by high molecular weight, do not have the physico-chemical properties required for passive diffusion across the blood brain barrier (BBB). The prodrug approach by lipidization of hydrophilic drugs generally allows to sensibly increase their permeability across BBB, even if this phenomenon is often not associated to an effective entry into the brain of the lipidized drugs. It has been understood that active efflux transporters (AET) can have a very important role in extruding from the brain not only prodrugs obtained by lipidization processes, but also lipophilic drugs. On the other hand, it has been also demonstrated carrier mediated transporters (CMT), able to transport essential nutrients and hormones from the bloodstream to the CNS, can be employed for the brain targeting of appropriated designed prodrugs. This approach consists on the chemical modification of a drug into a “pseudonutrient” or, differently, on drug conjugation to essential nutrients transported by CMT systems. This review focuses the molecular aspects that regulate the activity of the CMT and AET systems for the transport of their substrates, taking into account the in vitro and in vivo studies related to these transporters and, thus, the prodrug approaches useful to target the neuroactive agents in the central nervous systems are described. Among these, the molecular Trojan horses systems are briefly illustrated as carriers for the transport in the brain of large molecular weight neuroactive agents.
Prodrugs and Endogenous Transporters: Are They Suitable Tools for Drug Targeting into the Central Nervous System?
PAVAN, Barbara;DALPIAZ, Alessandro
2011
Abstract
Hydrophilic drugs, or neuroactive agents characterized by high molecular weight, do not have the physico-chemical properties required for passive diffusion across the blood brain barrier (BBB). The prodrug approach by lipidization of hydrophilic drugs generally allows to sensibly increase their permeability across BBB, even if this phenomenon is often not associated to an effective entry into the brain of the lipidized drugs. It has been understood that active efflux transporters (AET) can have a very important role in extruding from the brain not only prodrugs obtained by lipidization processes, but also lipophilic drugs. On the other hand, it has been also demonstrated carrier mediated transporters (CMT), able to transport essential nutrients and hormones from the bloodstream to the CNS, can be employed for the brain targeting of appropriated designed prodrugs. This approach consists on the chemical modification of a drug into a “pseudonutrient” or, differently, on drug conjugation to essential nutrients transported by CMT systems. This review focuses the molecular aspects that regulate the activity of the CMT and AET systems for the transport of their substrates, taking into account the in vitro and in vivo studies related to these transporters and, thus, the prodrug approaches useful to target the neuroactive agents in the central nervous systems are described. Among these, the molecular Trojan horses systems are briefly illustrated as carriers for the transport in the brain of large molecular weight neuroactive agents.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
