L-Type amino acid transporter 1 (LAT1)-utilizing prodrugs are carrier-selective despite having low affinity for...

L-Type amino acid transporter 1 (LAT1)-utilizing prodrugs has been designed to improve drug delivery and targeting into the brain or cancer cells, since LAT1 is highly and selectively expressed on the blood-brain barrier as well as over-expressed in several types of cancer. However, less is known about the affinity of these compounds for the secondary transport mechanisms. The aim of this study was to evaluate interactions of nine LAT1-utilizing prodrugs with organic anion transporting polypeptides (OATPs). These results showed that LAT1-utilizing prodrugs can indeed, interact with OATPs, although it was considered to be minor compared to LAT1; the K_m values of these compounds for LAT1 were 1-7 µM while the ones for OATPs were 73-406 µM. Moreover, utilization of LAT1 was 2-12-times more effective (compared as intrinsic clearance) than of OATPs, whose utilization seemed to be less significant at therapeutically used concentrations. According to these results, affinity for OATPs raised from the structural features of the parent drug moiety regardless of the structure of the promoiety. In conclusion, the present study shows that it is important to evaluate secondary transport mechanisms carefully, since they may have a role in pharmacokinetics of LAT1-utilizing prodrugs if LAT1 becomes saturated or un-functional.