Role of membrane transporters in drug delivery

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Tissues such as liver, kidney, brain and intestine expresses membrane transporters which play a vital role in drug absorption, distribution, metabolism and excretion. Understanding of functionality and molecular expression of drug transporters can prove to be of utmost importance in drug delivery or drug design by targeting specific transporter proteins. It’s a well-known fact that drug transporters play an important role in governing drug disposition which act as potential piece of information during the drug discovery and development process. By exploring the transporter functionality chances of delivering a therapeutic agent to the target organ enhances. Transporter targeted drug delivery helps in improving the bioavailability, controlling the elimination process and also avoid distribution to non-specific organs, hence diminishes the odds of toxic adverse effects. It is always suitable to choose a potential molecule which may or may not interact with the membrane transporters, depending on whether such an interaction is of any use or not. Activity of individual transport process can be examined by exploring the expression system of transporters. Therapeutic efficacy many important drugs, directly or indirectly, get affected due to genetic polymorphisms and drug-drug interactions involving membrane transporters which ultimately effects the pharmacokinetics of a drug molecule. During the drug discovery and development process, knowledge about the contribution of these transporters towards interindividual differences by regulating drug absorption, distribution, metabolism and excretion will act as an important tool. The objective of this dissertation project was to understand the role of hepatic uptake transporters (OATP-1B1 and -1B3) in governing the disposition of tyrosine kinase inhibitors (TKIs). Since selected TKIs are the substrates and/or inhibitors of OATP-1B1 and -1B3 expressed in hepatic tissue, these compounds can be regarded as molecular targets for transporter mediated drug-drug interactions (DDIs). Any alteration in the function of these hepatic OATPs might account for the pharmacokinetic variability of TKIs. These finding also provide the basis of further pre-clinical and clinical studies investigating the transporter based DDI potential of TKIs.
As a secondary aim of this investigation we developed novel pentablock (PB) copolymer nanoparticles of pazopanib for treatment of ocular neovascularization. Our results indicated that PB copolymer based drug delivery systems can serve as a platform technology for drug discovery and development of sustained release therapy along with evasion of drug efflux for the treatment of ocular neovascularization. This drug delivery system can also be utilized for other chronic diseases as well.
We also investigated the presence of ascorbic acid-specific transport system and delineate the functional and molecular aspects of vitamin C transporter (SVCT2) in ocular and breast cancer cells. SVCT2 system can be targeted for the design of ascorbic acid prodrugs or for NPs surface modified with ascorbic acid to achieve enhanced permeability for highly potent but poorly bioavailable drugs by evading drug efflux in the treatment of cancer and ocular diseases.
Interaction of TKIs with hepatic OATP-1B1 and -1B3 delineates the role of hepatic uptake transporters in drug disposition and drug-drug interactions. These OATP transporters in conjunction with the efflux proteins (P-gp, MRP and BCRP) may eventually decide on the overallflux/loss of the therapeutic agents within the hepatic tissue. Similary, functionality of membrane tranporters have been exploited and examined in terms of drug delivery. Pazopanib encapsulated nanoparticles of novel pentablock polymers were successful in bypass drug efflux mediated via efflux proteins. Also, influx transporters (vitamin C transporter, SVCT2) on ocular cell lines can be further utilized as a potential target for enhancing absorption and permeability of AAconjugated drugs or drug delivery systems by evading drug efflux.

Development and application of cheminformatics approaches

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In the past several decades, the development of efficient and effective in vitro assays has increased the demand for novel techniques to process experimental data into knowledge to facilitate drug discovery and environmental toxicity assessment. Due to diverged objectives, the analysis of pharmaceutical and toxicological data requires different strategies and tools. This dissertation describes the development and application of cheminformatics approaches for both the identification of potential drug candidates and the evaluation of chemicals’ adverse effects, with various foci and methods in each project.
In the pharmaceutical field, cheminformatics is popularly used for in silico modeling of absorption, distribution, metabolism, and excretion properties, e.g., blood-brain barrier (BBB) permeability. In this dissertation, we applied combinatorial quantitative structure-activity relationship (QSAR) modeling workflow to develop BBB permeability models with high predictive accuracy.
In order to accelerate drug discovery, new cheminformatics approaches are needed to improve the success rate and hit novelty of high-throughput screening (HTS). To this end, we developed internally validated and externally predictive QSAR models for antimalarial activity. The QSAR-based virtual screening prioritized chemicals in HTS libraries for biological evaluation, and greatly improved hit rate of experimental testing. Resulting hits were highly structurally diverse and contained novel scaffolds.
Unlike drug discovery, environmental toxicity assessment focuses on complex and mostly unknown biological events which are time-consuming and costly. Consequently, great efforts have been made to utilize in vitro and in silico predictors to forecast potential human toxicity of chemicals. We found that by employing an “in vitro-in vivo” extrapolation, the predictive accuracy of QSAR models of in vivo toxicity was improved.
Another growing public safety concern is endocrine disrupting compounds (EDCs), which may cause severe adverse effects on the health of humans and wildlife. The use of computational predictors to pick candidates for further endocrine disruption testing could significantly reduce the experimental cost. Therefore, I combined both ligand-based and structure-based virtual screening to identify potential EDCs that act via estrogen receptor.
In summary, the cheminformatics approaches I developed and applied successfully fulfilled the different objectives of drug design and chemical toxicity evaluation, and thus facilitate drug discovery and environmental toxicity assessment.