Comment on: “The pharmacokinetics of metformin in patients receiving intermittent haemodialysis” by Sinnappah et al
Abstract
Based on a population pharmacokinetic model, Sinnappah et al.1 have recently suggested that oral metformin HCl doses of 250–500 mg post-dialysis or 250 mg daily should be safe to use in patients receiving intermittent haemodialysis. While stating variously that the drug is ‘cleared entirely’ or ‘almost cleared entirely’ by the kidneys, their model incorporated a non-renal clearance ‘to capture unabsorbed and scant elimination by other routes’. Incomplete oral bioavailability was already incorporated in the model. This uncertainty underlines the need to clarify whether or not metformin undergoes some metabolism and to consider the impact of an ultra-long extensive distribution process on its accumulation and removal.2, 3 The tissue distribution of metformin involves active import by organic cation transporters4 and is suggested to account for a 21% shortfall in urinary recovery of unchanged drug at 72 h after intravenous dosage.2, 5 Based on the inhibition (IC50) of NADH: ubiquitone oxidoreductase, metformin is estimated to be concentrated 1000-fold in mitochondria relative to extracellular fluid.6 If there is negligible renal and metabolic clearance, no biliary/intestinal secretion,5 protracted distribution and haemodialysis over 4–6 h every 44 h removes only 9–35% of a dose,1 then replacement with a dose of 250–500 mg, even though only half of it may be absorbed,5 would be predicted to result in excessive accumulation eventually. Relatively small increments in trough plasma…
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