The Effect of Novel Promoter Variants in MATE1 and MATE2 on the Pharmacokinetics and Pharmacodynamics of Metformin

Interindividual variation in response to metformin, first‐line therapy for type 2 diabetes, is substantial. Given that transporters are determinants of metformin pharmacokinetics, we examined the effects of promoter variants in both multidrug and toxin extrusion protein 1 (MATE1) (g.–66T→C, rs225228...

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Published in:Clinical pharmacology and therapeutics 2013-02, Vol.93 (2), p.186-194
Main Authors: Stocker, S L, Morrissey, K M, Yee, S W, Castro, R A, Xu, L, Dahlin, A, Ramirez, A H, Roden, D M, Wilke, R A, McCarty, C A, Davis, R L, Brett, C M, Giacomini, K M
Format: Article
Language:English
Subjects:
Biological and medical sciences
Diabetes Mellitus, Type 2 - genetics
Diabetes Mellitus, Type 2 - metabolism
Female
Genotype
Humans
Hypoglycemic Agents - pharmacokinetics
Hypoglycemic Agents - pharmacology
Kidney - drug effects
Kidney - metabolism
Male
Medical sciences
Metformin - pharmacokinetics
Metformin - pharmacology
Organic Cation Transport Proteins - genetics
Organic Cation Transport Proteins - metabolism
Pharmacology. Drug treatments
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Summary:Interindividual variation in response to metformin, first‐line therapy for type 2 diabetes, is substantial. Given that transporters are determinants of metformin pharmacokinetics, we examined the effects of promoter variants in both multidrug and toxin extrusion protein 1 (MATE1) (g.–66T→C, rs2252281) and MATE2 (g.–130G→A, rs12943590) on variation in metformin disposition and response. The pharmacokinetics and glucose‐lowering effects of metformin were assessed in healthy volunteers (n = 57) receiving metformin. The renal and secretory clearances of metformin were higher (22% and 26%, respectively) in carriers of variant MATE2 who were also MATE1 reference (P < 0.05). Both MATE genotypes were associated with altered post‐metformin glucose tolerance, with variant carriers of MATE1 and MATE2 having an enhanced (P < 0.01) and reduced (P < 0.05) response, respectively. Consistent with these results, patients with diabetes (n = 145) carrying the MATE1 variant showed enhanced metformin response. These findings suggest that promoter variants of MATE1 and MATE2 are important determinants of metformin disposition and response in healthy volunteers and diabetic patients. Clinical Pharmacology & Therapeutics (2013); 93 2, 186–194. doi:10.1038/clpt.2012.210
ISSN:0009-9236
1532-6535
DOI:10.1038/clpt.2012.210