Abstract
The antidiabetic agent glyburide (glibenclamide) is frequently used for the treatment of type II diabetes and is increasingly being used for the treatment of gestational diabetes. Evidence suggests that BCRP/ABCG2 expressed in the placenta protects the fetus against the accumulation of glyburide. A number of studies have investigated the significance of several single-nucleotide polymorphisms (SNPs) in the ABCG2 gene. Associations between the Q141K (C421A) single nucleotide polymorphism and ABCG2 protein expression, membrane surface translocation, efflux activity, or ATPase activity have been demonstrated. Therefore, alterations in glyburide transport across the placenta, resulting in increased fetal glyburide exposure, may be seen in individuals carrying the C421A allele. The purpose of this study is to investigate whether the Q141K SNP causes alterations in ABCG2-mediated glyburide transport. Glyburide accumulation assays were carried out with stably transfected HEK-293 cells expressing wild-type ABCG2 (R482) and polymorphic ABCG2 (Q141K). Glyburide kinetic parameters were determined for comparison of wild-type and SNP ABCG2 activity by simultaneously fitting data for ABCG2 expressing cells (saturable transport) and empty vector expressing cells (nonsaturable transport) by non-linear regression analysis. The apparent Kt and Vmax values for the transfected HEK-293 cells expressing the polymorphic variant (Q141K) of ABCG2 were significantly higher than those values determined for the wild type ABCG2 expressing cells (p<0.05). Our results indicate that the Q141K variant of ABCG2 may have the potential to alter the placental pharmacokinetics of glyburide used in pregnancy.
Footnotes
- Received October 14, 2009.
- Accepted February 16, 2010.
- The American Society for Pharmacology and Experimental Therapeutics