Mixed outcomes from clinical trials that tested the effect of combining statins and fenofibrate, posed a challenge in using this antidyslipidemic medication. One significant challenge of using fenofibrate is the high inter-subject variability in lipid response, which can range from -82 to 132% for triglyceride change from baseline. This magnitude of variability suggests the involvement of non-environmental factors, such as the genetic source of the variability. We identified a genetic variation, UGT2B7 A-327G, harbored in a key metabolizing gene of fenofibrate. It was the source of a 17% differences in the percent-change of triglycerides, post-fenofibrate treatment, between UGT2B7 A-327G genotype groups. We hypothesized that this lipid response variation was due to UGT2B7 A-327G's effect on serum concentration of fenofibrate (exposure). We confirmed this hypothesis by conducting Fenofibrate and the Pharmacogenetic Impact (FPI) study, a pharmacokinetic study aimed at explicitly quantifying the effect of UGT2B7 A-327G on fenofibric acid serum concentration. Furthermore, we discovered that UGT2B7 A-327G modulated the uricosuric effect of fenofibrate in a same manner it modulated the antidyslipidemic response. We considered this as another confirmation of the importance of this genetic variation on fenofibrate's response. We also confirmed that another genetic variation, UGT1A1*28, had an effect on serum concentration of fenofibric. In contrast to UGT2B7 A-327G, UGT1A1*28 did not cause a lipid response variation. However, UGT1A1*28 did modulated the effect of fenofibrate on bilirubin level. Recognizing and quantifying the effect of these genetic variations will assist in optimizing fenofibrate treatment.
University of Minnesota Ph.D. dissertation. September 2012. Major: Experimental & Clinical Pharmacology. Advisor: Dr. Robert J Straka. 1 computer file (PDF); x, 164 pages.
Studies investigating the impact of select genotypes on the pharmacological effect of fenofibrate.
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