Abstract
Active transport of drug into milk is a major concern in breastfeeding. Abcg2 plays a critical role in drug transfer into rat milk which is consistent with evidence in humans. Although it is estimated that about half of all therapeutic agents are chiral, there have been few reports of stereoselective interactions with ABCG2. The purpose of this study was to investigate the interaction of pantoprazole (PAN) isomers with Abcg2 in in vitro and in vivo experiments. Pantoprazole isomer flux was characterized using Abcg2 -MDCKII cells in Transwells. In a crossover design, lactating Sprague-Dawley lactating rats were used to study PAN accumulation in milk after an i.v. infusion of pantoprazole mixture after Abcg2 inhibitor (GF120918). Samples were analyzed by HPLC/LC-MS. The results indicated that pantoprazole isomers were transported in an identical fashion in vector-MDCKII cell lines, whereas a significant difference in flux was observed in Abcg2-MDCKII cell line. The administration of GF120918 slightly increased the concentration of both isomers in serum, but no statistical difference was observed. However, the systemic clearance of (+) PAN (0.57±0.1) was larger than (-) PAN (0.44±0.12) (p<0.01). Milk to serum ratio of (-) PAN (1.36±0.20) was 2.5 fold greater than that of (+) PAN (0.54±0.09) (p<0.01). Administration of GF120918 decreased M/S of (-) PAN to 0.50±0.08 (p<0.001) and (+) PAN to 0.38±0.07 (p>0.05). In conclusion, Abcg2 interacts stereoselectively with PAN isomers which is responsible for their differential accumulation in milk. Stereoselective transport of ABCG2 may have broader consequences in drug disposition.
- ABC transporters
- absorption
- drug clearance
- drug disposition
- drug distribution
- drug efflux
- drug transport
- protein binding
- transporters
- Received July 7, 2011.
- Accepted February 16, 2012.
- The American Society for Pharmacology and Experimental Therapeutics