AIMS:
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 modelling was developed to identify covariates associated with systemic exposure to
metformin, accessed by the area under the
plasma concentration-
time curve, between 0 and 48 h (AUC0-48h ), after single oral doses of
metformin (500 or 1000 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 AUC0-48h '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%
confidence interval; P = 6.10-26 , t test). Multivariate modelling revealed that
metformin AUC0-48h increased with age,
food and carriage of rs12208357 in SLC22A1 but was inversely associated with
body surface area and individual proportions of African ancestry.
CONCLUSIONS:
A pharmacogenetic marker in OCT1 (SLC22A1 rs12208357), combined with demographic covariates (age,
body surface area and individual proportion of African ancestry) and a
food effect explained 29.7% of the variability in
metformin AUC0-48h .