Using a limited sampling strategy to investigate the interindividual pharmacokinetic variability in metformin: A large prospective trial

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Abstract

Aims: Recently a limited sampling strategy (LSS) for determination of metformin' pharmacokinetics was developed. The LSS utilizes the plasma concentration of metformin 3 and 10 hours after oral intake of a single dose to estimate the area under the concentration–time curve up to 24 hours (AUC 0–24h). The main purpose of this study was to support the feasibility of this strategy in a large prospective trial. Methods: Volunteers orally ingested two 500-mg tablets of metformin hydrochloride. A blood sample was drawn three and ten hours after the ingestion. Urine was collected for 0–10 and 10–24 hours and urine volumes recorded. The AUC 0–24h was calculated using the equation AUC 0–24h = 4.779 * C 3 + 13.174 * C 10. Additionally, all participants were genotyped for the single-nucleotide polymorphism A270S in OCT2, g.-66 T > C in MATE1, R61C, G465R, G401S and the deletion M420del in OCT1. Results: In total, 212 healthy volunteers participated. The median (25th - 75th interquartile range) AUC 0 − 24h, CL renal, C 3 and C 10, were 10 600 (8470–12 500) ng* hr* mL −1, 29 (24–34) L* hour −1, 1460 (1180–1770) and 260 (200–330) ng* mL −1, respectively, which is in agreement with our previous results. GFR i was correlated with metformin AUC and CL renal (P <.001). As expected, we found a great pharmacokinetic interindividual variability among the volunteers and no effect of the OCT1 genotype on the AUC 0 − 24h. We were unable to reproduce our previous finding of a gene–gene interaction (OCT2 and MATE1) effect on CL renal in this cohort. Conclusion: This study further supports the use of the 2-point LSS algorithm in large pharmacokinetic trials.

Original languageEnglish
JournalBritish Journal of Clinical Pharmacology
Volume87
Issue number4
Pages (from-to)1963-1969
ISSN0306-5251
DOIs
Publication statusPublished - Apr 2021

Keywords

  • MATE1
  • OCT1
  • OCT2
  • limited sampling strategy
  • metformin
  • pharmacokinetics

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