Prodrug Approach to Improve Oral and Brain Absorption of HIV Protease Inhibitor, Lopinavir

The main objective of this project is to develop prodrug strategies to circumvent efflux pumps such as P-glycoprotein (P-gp) and multidrug resistance associated proteins (MRPs), thereby enhancing oral and brain absorption of lopinavir (LPV). Oral absorption of LPV is severly limited due to low aqueous solubility, intestinal efflux by P-gp and MRP2 and extensive hepatic metabolism (CYP3A4 enzymes). Furthermore, brain LPV absorption is poor due to high efflux by P-gp and MRP2 at blood-brain barrier (BBB), plasma protein binding (99%) and extensive CYP3A4 metabolism. Hence, to improve oral and brain absorption of LPV simultaneously, di-peptide and amino acid prodrugs have been developed and evaluated. Prodrugs displayed higher affinity towards influx transporters and efficiently circumvented P-gp and MRP2 efflux pumps. These compounds generated significantly higher aqueous solubility and permeability rates relative to LPV. Prodrugs displayed lower affinity towards CYP3A4 enzymes. Oral absorption of prodrugs was significantly higher compared to LPV in rats. Moreover, mean residence time of prodrugs was significantly higher compared to LPV indicating that prodrugs may stay for a longer time period in plasma. Prodrugs were observed to possess lower binding affinity towards plasma proteins. Di-peptide prodrug underwent enzymatic hydrolysis in sequential manner to produce amino acid prodrug and LPV in plasma. This regeneration is a critical and rate determining step as amino acid prodrug can permeate BBB by targeting amino acid transporters from systemic circulation. Rifampicin treated rat brain capillary endothelial cells (Rif-RBE4) co-cultured with astrocytes appeared to be an excellent in vitro cell culture model to study permeabilities of LPV and prodrugs across BBB. Prodrugs generated higher permeability rates across Rif-RBE4 cocultured with astroctyes relative to LPV. This result demonstrates that prodrugs may produce higher permability rates across blood-brain interfaces relative to LPV. Brain absorption of prodrugs was also higher compared to LPV. Importantly, prodrugs were able to regenerate LPV following brain absorption as evident in brain microdialysis study. Based on results obtained from this study, it is apparent that transporter targeted prodrug modification may be a viable strategy to improve oral as well as brain absorption of LPV following oral administration

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Pharmaceutical Sciences (UMKC)

Grantor

University of Missouri--Kansas City

Year dc:date.issued

2014

Author dc:creator

• Patel, Mitesh

Advisor dc:contributor.advisor

• Mitra, Ashim K., 1954-

Handle dc:identifier.uri

https://hdl.handle.net/10355/43907

OAI identifier oai:identifier

oai:mospace.umsystem.edu:10355/43907