Question: 

The p-glycoprotein (Pgp) actively transports many diverse substrates out of tumor cells leading to a multidrug resistant phenotype. Since some of these substrates have complex structures the question arises whether the chirality of the molecule has an impact on Pgp-mediated transport and therefore affects the distribution of these drugs in vivo.

Methods: 

The study was performed using a ⁶⁸Ga-labeled tracer (the Schiff'base ligand complex [⁶⁸Ga]MF6.MZ) which acts as a substrate of Pgp. During Ga-complexation the molecule forms two stereoisomers which can be separated by HPLC. The Pgp-transport rate was measured in vitro by tracer uptake into tumor cells. In vivo distribution was assessed in tumor-bearing animals in which the tracer concentration was determined in various organs 60 min after i.v. injection.

Results: 

The intracellular concentration of the (+)-[⁶⁸Ga]MFL6.MZ-isomer was markedly lower than for the (-)-isomer indicating that the (+)-ligand is transported more efficiently. Adding excess amount of the unlabeled compound increased the intracellular tracer concentration as a result of a substrate competition. In vivo biodistribution showed that the concentration of the (+)-isomer was higher in most tissues (however not in the liver). Surprisingly the intratumoral concentration of the (+)-isomer was markedly higher in contrast to the results obtained in cell culture.

Conclusions: 

The results clearly show that the transport rate of the p-glycoprotein depends on the chirality of the substrate. The data also illustrate that cell culture experiments cannot be directly transferred to the in vivo situation because of other transport mechanisms (e.g., tissue perfusion) or different drug transporters (e.g., MRP1) which might play a role.