Significant impact of time-of-day variation on metformin pharmacokinetics

Abstract

Aims/hypothesis The objective was to investigate if metformin pharmacokinetics is modulated by time-of-day in humans using empirical and mechanistic pharmacokinetic modelling techniques on a large clinical dataset. This study also aimed to generate and test hypotheses on the underlying mechanisms, including evidence for chronotype-dependent interindividual differences in metformin plasma and efficacy-related tissue concentrations. Methods A large clinical dataset consisting of individual metformin plasma and urine measurements was analysed using a newly developed empirical pharmacokinetic model. Causes of daily variation of metformin pharmacokinetics and interindividual variability were further investigated by a literature-informed mechanistic modelling analysis. Results A significant effect of time-of-day on metformin pharmacokinetics was found. Daily rhythms of gastrointestinal, hepatic and renal processes are described in the literature, possibly affecting drug pharmacokinetics. Observed metformin plasma levels were best described by a combination of a rhythm in GFR, renal plasma flow (RPF) and organic cation transporter (OCT) 2 activity. Furthermore, the large interindividual differences in measured metformin concentrations were best explained by individual chronotypes affecting metformin clearance, with impact on plasma and tissue concentrations that may have implications for metformin efficacy. Conclusions/interpretation Metformin’s pharmacology significantly depends on time-of-day in humans, determined with the help of empirical and mechanistic pharmacokinetic modelling, and rhythmic GFR, RPF and OCT2 were found to govern intraday variation. Interindividual variation was found to be partly dependent on individual chronotype, suggesting diurnal preference as an interesting, but so-far underappreciated, topic with regard to future personalised chronomodulated therapy in people with type 2 diabetes. Graphical abstract

Morning exercise and pre-breakfast metformin interact to reduce glycaemia in people with Type 2 Diabetes: a randomized crossover trial

“…For example, compared with the fasting state, bioavailability of metformin is 24% lower, and the peak concentration delayed about 37 min when an 850 mg tablet is administered with food [18]. Additionally, metformin’s pharmacology significantly depends on time-of-day in humans, which may be related to glomerular filtration rate, renal plasma flow (RPF) and renal organic cation transporter (OCT) 2 activity [19]. Although the half-life of metformin in the blood is relatively long (∼18 hours depending on dose/method [20]), less is known regarding accumulation in skeletal muscle, a key organ in the response to exercise [1].…”

Circadian Dysfunction in Adipose Tissue: Chronotherapy in Metabolic Diseases

“…Metformin drives a phenotypic shift away from fat accumulation via AMPK-NAMPT-SIRT1-mediated alterations in clock components, providing support for chronotherapeutic approaches to the treatment of obesity [172]. Additionally, metformin's human pharmacokinetics are affected by interindividual variation and time of day due to oscillations in glomerular filtration rate (GFR), renal plasma flow (RPF), and organic cation transporter 2 (OCT2) activity, indicating that the individual chronotype may be important for metformin's chronotherapy [173].…”