Pharmacogenomics of Sulfonylureas and Glinides on ATP-Sensitive Potassium Channel
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Abstract
The common ATP-sensitive (KATP) channel variants E23K and S1369A, found in the KCNJ11 and ABCC8 genes respectively, form a haplotype that is associated with an increased risk for type 2 diabetes. Our previous studies showed that KATP channel inhibition by the A-site sulfonylurea gliclazide was increased in the K23/A1369 haplotype. Therefore, I studied the pharmacogenomics of eight more clinically used sulfonylureas and glinides to determine their structure activity relationships in KATP channels containing either the E23/S1369 non-risk or K23/A1369 risk haplotypes by utilizing patch-clamp technique. The results demonstrate that the ring-fused pyrrole moiety in several A-site drugs likely underlies the observed inhibitory potency of these drugs on KATP channels containing the K23/A1369 risk haplotype. It may, therefore, be possible to tailor existing therapies or design novel drugs that display increased efficacy in type 2 diabetes patients homozygous for these common KATP channel haplotypes.