M. Walton1, J. Wagner1, B. Hagenbuch2; 1Children's Mercy Hospital, Kansas City, Mo, United States, 2University of Kansas Medical Center, Kansas City, KS, United States.
Pediatric Cardiologist, Clinical Pharmacology Fellow Children's Mercy Hospital Kansas City, Missouri, United States
Background: Aortic root dilation, a common manifestation of the connective tissue disorder, Marfan syndrome, is associated with catastrophic aortic root dissection. To mitigate this risk, prophylactic anti-hypertensive therapy is recommended. Atenolol, a selective beta-1 receptor antagonist, is commonly utilized. Unfortunately, patients continue to have suboptimal response. Prior studies demonstrated response variability associated with gene variants within the beta-1 receptor gene. However, analysis related to genes responsible for atenolol disposition lacks. The human organic cation uptake transporters (OCT) 2 and 1, encoded by the SLC22A2 and SLC22A1 genes, are influx transporters involved in the uptake of atenolol, as well as the antidiabetic drug, metformin. Genetic variation in OCT2 and OCT1 affects the pharmacokinetics of metformin. However, there are no studies evaluating the effects of OCT2 and OCT1 genetic variability on atenolol uptake and drug disposition. Thus, the objective of this MARFAN study is to determine the role of genetic variants on the cellular uptake and clearance of atenolol, which may then affect drug disposition and clinical effect. Methods: Transiently transfected OCT2 and OCT1 cell assays will be used to perform time-dependent radioactive atenolol cellular uptake experiments, to then generate kinetics parameters. Site-directed mutagenesis will generate plasmid DNA for cellular transfection to assess OCT2 and OCT1 genetic polymorphisms influence on uptake. Results: In initial experiments using reference genotype OCT1 cells, MPP (positive control agent) and atenolol uptake was less than expected. In troubleshooting, I compared uptake in cell lines stably expressing OCT1 versus transiently transfected. Uptake for both agents was greater in stable cells compared to the transiently transfected cells. See Figure 1. Conclusion: While still in the data collection phase, the protocol has been established and successful. This study potentially will provide a mechanistic understanding of polymorphisms associated with OCT2 and OCT1, and function to individualize pharmacologic therapy for not only atenolol, but other OCT2 and OCT1-dependent drugs.