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• W2890299754 abstract "Metformin is the first-line treatment for type 2 diabetes mellitus given it is superior to other agents with respect to improving glycaemic control and cardiovascular outcomes. Metformin is entirely eliminated by the kidney, partially by glomerular filtration, but predominantly by tubular secretion 1. Metformin's pharmacokinetics are largely due to the active drug transporters [organic cation transporters (OCT), plasma membrane monoamine transporters (PMAT) and multidrug and toxin extrusion transporters (MATE)]; thus, polymorphisms in transporter function and drug–drug interactions induce interindividual differences in pharmacokinetics 1, 2. Increasing data have described the pharmacokinetics of metformin in patients with chronic kidney disease (CKD) and indicated that it can be safely prescribed to such patients with appropriate dose adjustments 3, 4. However, impaired kidney function increases the risk of complications from metformin therapy, notably metformin-associated lactic acidosis (MALA), which is important given the mortality from MALA is potentially high 5, 6. MALA is also seen in the context of an acute overdose of metformin, where it is sometimes called metformin-induced lactic acidosis (MILA) if this is the sole reason for the lactic acidosis. The report by Chiew et al. 7 describes the management and outcomes following an acute (‘massive’; approximately 132 g) overdose of extended release metformin and other medications. The peak metformin concentration was 292 mg l−1 at 8 h postingestion (therapeutic: 1.5–3.0 mg l−1). The admission was complicated by shock, anuric acute kidney injury (AKI) and severe lactic acidosis with nadir pH 6.83 and peak lactate 30 mmol l−1. In addition to supportive care, gastrointestinal decontamination, inotropic and vasopressor support and admission to an intensive care unit, the patient was consecutively administered two types of extracorporeal treatments and the outcome was favourable. Two key roles for extracorporeal treatments are the removal of metformin in the context of AKI and the correction of severe acidaemia. Extracorporeal treatments such as haemodialysis are commonly utilized treatments for MALA and consensus-based recommendations for the indications for extracorporeal treatments were recently published by the EXTRIP group 5. However, the EXTRIP recommendations were largely based on a very low level of evidence and data from patients on chronic metformin therapy, so it is not certain whether different considerations are required for the management of an acute metformin overdose. For example, a key recommendation is the first-line use of intermittent haemodialysis (IHD) over continuous renal replacement therapy (CRRT) 5, but haemodynamic instability is not uncommon in patients with severe MALA 5, 6, particularly in the context of an acute overdose and with coingestants that may also affect blood pressure or kidney function, in this case perindopril, ibuprofen and indapamide. CRRT is usually preferred in haemodynamically unstable patients; however, metformin is cleared more efficiently with IHD; thus, it is not certain whether choosing CRRT over IHD, or vice versa, will be of most overall benefit. Therefore, additional data describing outcomes from acute metformin poisoning and the effect of various treatments are of great interest. The determination of pharmacokinetics following an acute poisoning is potentially challenging due to uncertainties in alterations of absorption, distribution and elimination. Shock and vasopressor therapy lead to reduced organ perfusion, including to the gut, potentially reducing bioavailability and rate of absorption of metformin 8. Changes in active drug transporter function due to shock, uraemia, acidaemia and any dose dependencies are poorly defined. Endogenous kidney clearance is uncertain and variable in the context of AKI, particularly oligoanuria as in this case. Extracorporeal treatments potentially remove a larger proportion of the bioavailable dose if commenced during the absorption and disposition phases for drugs with a large volume of distribution. For example, a volume of distribution exceeding 1–2 l kg−1 is considered significant because a large proportion of the dose is located outside the vascular space following drug distribution and, therefore, not readily accessible to the effect of the extracorporeal treatment. This is relevant for metformin which has a volume of distribution from 1 up to 5 l kg−1 1 and because IHD significantly increases overall clearance in anuric patients. IHD clearance is approximately 170% higher than non-IHD clearance (composed of clearance due to extravascular partitioning and CRRT) according to Chiew et al. 7 and 75% higher than the intercompartmental clearance determined in predominantly CKD patients 3, 9, 10. Finally, extrapolating from data on erythrocyte partitioning, metformin slowly redistributes from the intracellular space to the plasma 10, 11 so IHD may not shorten the recovery time from an established MALA/MILA. Therefore, drug removal prior to extravascular distribution is potentially favourable and most likely to be achieved with IHD. Different methods are available for quantifying pharmacokinetics in acute poisoning, and the extent to which they are influenced by extracorporeal treatments. The report by Chiew et al. 7 utilized a whole-body approach based on serial plasma concentrations. The accuracy of parameters determined by this method is improved with frequent and multiple blood samples and when pharmacokinetics are first order. Of the eight samples used for the analysis, three were collected when there was ongoing urine output so endogenous clearance was likely to have contributed, but is anticipated to be low. There is likely to have also been a contribution from distribution of metformin from the plasma compartment to other tissues. Metformin displays two- or three-phase concentration-time curves due to distribution into multiple compartments, including erythrocytes, liver and other organs 1. The apparent clearances (CL/F) calculated by Chiew et al. 7 were 22.2 l h−1 during IHD and 8.2 l h−1 during CVVHD. As the authors discuss, the CL/F values in their case exceed those reported for IHD and CRRT previously. However, if we consider the IHD treatment and the minimal release of metformin from the erythrocyte compartment during dialysis 10, the maximum clearance of metformin possible based on a reported blood flow of 250 ml min−1 and a haematocrit of 40% is 9 l h−1. It should be remembered that the apparent clearances as reported by Chiew et al. 7 should be adjusted for bioavailability. If it can be assumed that bioavailability may be substantially below the 56 ± 16% reported in various studies 1, given that the overdose involved an extended-release form of metformin, and that charcoal and whole bowel irrigation were administered, with white tablet effluent observed, then the apparent clearances reported seem entirely within reason. To more accurately quantify the extent to which the various dialysis modalities can remove metformin in such cases of acute overdose, the collection of urine (if available) and dialysate effluent for assay, alongside plasma, should be considered. When compared to systemic clearance based on techniques as used by Chiew et al. 7, the proportion of clearance due to these specific routes and its potential clinical significance can be determined. This will help clarify the specific indications for extracorporeal treatments in MALA. Unfortunately, it is time-consuming, complex and resource-intensive to collect these additional samples in the acute context, but guidance is available to maximize data collection 12. As a final point, Chiew et al. 7 describe the successful use of IHD with improvement in clinical outcomes, despite the patient simultaneously requiring inotropic and vasopressor therapy to maintain an adequate blood pressure. Note that haemodynamic instability is less common from IHD when net ultrafiltration is minimal, which is commonly achievable with acute poisoning since patients are more likely hypovolaemic. Therefore, this publication should increase the confidence of clinicians to trial IHD upfront because it is the more effective extracorporeal modality in patients with MALA, regardless of concurrent haemodynamic instability. Theoretically, earlier initiation of IHD, prior to distribution of metformin from the plasma to erythrocytes and extravascular tissues, may remove a higher proportion of the dose and reduce the severity of MALA even further. Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 13, and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 14. There are no competing interests to declare. D.M.R. is a recipient of the Jacquot Research Establishment Fellowship, Royal Australasian College of Physicians and the Clinician ‘Buy-Out’ Program, St Vincent's Centre for Applied Medical Research." @default.
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• W2890299754 title "Complex decisions in the use of extracorporeal treatments in acute metformin overdose: which modality, when and how to measure the effect" @default.
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