INFLUENCE OF PHARMACOGENETIC POLYMORPHISMS AND DEMOGRAPHIC VARIABLES ON METFORMIN PHARMACOKINETICS IN AN ADMIXED BRAZILIAN COHORT

Abstract

Aim

To identify pharmacogenetic and demographic variables that influence the systemic exposure to metformin in an admixed Brazilian cohort.

Methods

The extreme discordant phenotype was used to select 106 data sets from nine metformin bioequivalence trials, comprising 256 healthy adults. Eleven single-nucleotide polymorphisms in SLC22A1, SLC22A2, SLC47A1 SLC47A2 and in transcription factor SP1 were genotyped and a validated panel of ancestry informative markers was used to estimate the individual proportions of biogeographical ancestry. Two-step (univariate followed by multivariate) regression modeling was developed to identify covariates associated with systemic exposure to metformin, accessed by the area under the plasma concentration versus time curve, between 0 and 48 h (AUC_0-48h), after single oral doses of metformin (500 or 1,000 mg).

Results

The individual proportions of African, Amerindian and European ancestry varied widely, as anticipated from the structure of the Brazilian population The dose-adjusted, log-transformed AUC_0-48h´s (ng.h.ml^-1.mg^-1) differed largely in the two groups at the opposite ends of the distribution histogram, namely 0.82, 0.79-0.85 and 1.08, 1.06-1.11 (mean, 95%CI; p = 6.10^-26, t test). Multivariate modeling revealed that metformin AUC_0-48h increased with age, food and carriage of rs12208357 in SLC22A1 but was inversely associated with body surface area (BSA) and individual proportions of African ancestry.

CONCLUSIONS

A pharmacogenetic marker in OCT1 (SLC22A1 rs12208357), combined with demographic covariates (age, BSA and individual proportion of African ancestry) and a food effect explained 29.7% of the variability in metformin AUC_0-48h.

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