Timothy J. Furlong

Clinical Pharmacokinetics of Metformin

Metformin is widely used for the treatment of type 2 diabetes mellitus. It is a biguanide developed from galegine, a guanidine derivative found in Galega officinalis (French lilac). Chemically, it is a hydrophilic base which exists at physiological pH as the cationic species (>99.9%). Consequently, its passive diffusion through cell membranes should be very limited. The mean ± SD fractional oral bioavailability (F) of metformin is 55 ± 16%. It is absorbed predominately from the small intestine.Metformin is excreted unchanged in urine. The elimination half-life (t1/2) of metformin during multiple dosages in patients with good renal function is approximately 5 hours. From published data on the pharmacokinetics of metformin, the population mean of its clearances were calculated. The population mean renal clearance (CLR) and apparent total clearance after oral administration (CL/F) of metformin were estimated to be 510 ± 130 mL/min and 1140 ± 330 mL/min, respectively, in healthy subjects and diabetic patients with good renal function. Over a range of renal function, the population mean values of CLR and CL/F of metformin are 4.3 ± 1.5 and 10.7 ± 3.5 times as great, respectively, as the clearance of creatinine (CLCR). AS the CLR and CL/F decrease approximately in proportion to CLCR, the dosage of metformin should be reduced in patients with renal impairment in proportion to the reduced CLCR.The oral absorption, hepatic uptake and renal excretion of metformin are mediated very largely by organic cation transporters (OCTs). An intron variant of OCT1 (single nucleotide polymorphism [SNP] rs622342) has been associated with a decreased effect on blood glucose in heterozygotes and a lack of effect of metformin on plasma glucose in homozygotes. An intron variant of multidrug and toxin extrusion transporter [MATE1] (G>A, SNP rs2289669) has also been associated with a small increase in antihyperglycaemic effect of metformin. Overall, the effect of structural variants of OCTs and other cation transporters on the pharmacokinetics of metformin appears small and the subsequent effects on clinical response are also limited. However, intersubject differences in the levels of expression of OCT1 and OCT3 in the liver are very large and may contribute more to the variations in the hepatic uptake and clinical effect of metformin.Lactic acidosis is the feared adverse effect of the biguanide drugs but its incidence is very low in patients treated with metformin. We suggest that the mean plasma concentrations of metformin over a dosage interval be maintained below 2.5 mg/L in order to minimize the development of this adverse effect.

Metformin therapy in patients with chronic kidney disease.

Metformin therapy is limited in patients with chronic kidney disease (CKD) due to the potential risk of lactic acidosis. This open‐label observational study investigated metformin and lactate concentrations in patients with CKD (n = 22; creatinine clearances 15–40 ml/min) and in two dialysed patients. Patients were prescribed a range of metformin doses (250–2000 mg daily) and metformin concentrations were compared with data from healthy subjects (scaled to 1500 mg twice daily). A subset of patients (n = 7) was controlled on low doses of metformin (250 or 500 mg daily). No correlation between metformin and lactate concentrations was observed. Three patients had high lactate concentrations (>2.7 mmol/l) and two had high metformin concentrations (3–5 mg/l), but none had any symptoms of lactic acidosis. Reducing metformin dosage and monitoring metformin concentrations will allow the safe use of metformin in CKD, provided that renal function is stable.

Successful use of allopurinol in a patient on dialysis

We report the case of a man with chronic tophaceous gout who had end-stage renal failure secondary to the Alport syndrome. Following a failed kidney transplant, where urate deposition was a suspected contributor, the patient responded positively to consistent allopurinol therapy and regular haemodialysis sessions. Extensive and destructive tophi receded in size remarkably and the almost constant incidence of acute attacks of gout subsided. The patient has recently received a new kidney transplant and his plasma concentrations of urate are controlled well with allopurinol and he no longer experiences acute attacks of gout. While efficacious, adherence is critical for achieving the therapeutic effects of allopurinol even in end-stage renal disease.

Pharmacokinetics of Metformin in Patients Receiving Regular Hemodiafiltration

To the Editor: Metformin is first-line therapy for type 2 diabetes mellitus (T2DM). Concerns that metformin may accumulate and precipitate the severe adverse event lactic acidosis when kidney function is poor has led to its contraindication in patients with reduced kidney function. Most references discourage its use at a creatinine clearance , 30 mL/min. Recently, we showed that with appropriate dose reduction, metformin can be safely administered to patients with creatinine clearances as low as 15 mL/min without metformin or lactate concentrations increasing. One patient in this cohort was also on hemodiafiltration (HDF) and had no elevation of metformin or lactate concentrations. Previous studies investigating metformin in hemodialysis or HDF either lack detailed pharmacokinetic analysis of therapeutic doses or are in the context of metformin overdose and/or lactic acidosis. The aims of the present study were therefore to investigate the pharmacokinetics of metformin in diabetic patients receiving regular HDF and provide an initial examination of its safety in these patients. Four patients (HDF sessions thrice weekly) with T2DM were treated initially with metformin (500 mg, immediate-release formulation) after HDF (1,500 mg/wk). Pre-HDF blood samples were drawn on 6 occasions (end of weeks 1-4, 8, and 12) to measure biochemical parameters. Paired (before and after the hemodiafilter) serial blood samples (3-6 pairs) were collected over the course of each session to determine extracorporeal metformin

The pharmacokinetics of metformin and concentrations of haemoglobin A1C and lactate in Indigenous and non-Indigenous Australians with type 2 diabetes mellitus

AIMS To compare the pharmacokinetics of metformin between diabetic Indigenous (Aboriginal and Torres Strait Islander) and non-Indigenous patients. METHODS An observational, cross-sectional study was conducted on type 2 diabetic Indigenous and non-Indigenous patients treated with metformin. Blood samples were collected to determine metformin, lactate, creatinine and vitamin B12 concentrations and glycosylated haemoglobin levels. A population model was used to determine the pharmacokinetic parameters. RESULTS The Indigenous patients (median age 55 years) were younger than the non-Indigenous patients (65 years), with a difference of 10 years (95% confidence interval 6-14 years, P < 0.001). The median glycosylated haemoglobin was higher in the Indigenous patients (8.5%) than in the non-Indigenous patients (7.2%), with a difference of 1.4% (0.8-2.2%, P < 0.001). Indigenous patients had a higher creatinine clearance (4.3 l h(-1) ) than the non-Indigenous patients (4.0 l h(-1) ), with a median difference of 0.3 l h(-1) (0.07-1.17 l h(-1) ; P < 0.05). The ratio of the apparent clearance of metformin to the creatinine clearance in Indigenous patients (13.1, 10.2-15.2; median, interquartile range) was comparable to that in non-Indigenous patients (12.6, 9.9-14.9). Median lactate concentrations were also similar [1.55 (1.20-1.88) vs. 1.60 (1.35-2.10) mmol l(-1) ] for Indigenous and non-Indigenous patients, respectively. The median vitamin B12 was 306 pmol l(-1) (range 105-920 pmol l(-1) ) for the Indigenous patients. CONCLUSIONS There were no significant differences in the pharmacokinetics of metformin or plasma concentrations of lactate between Indigenous and non-Indigenous patients with type 2 diabetes mellitus. Further studies are required in Indigenous patients with creatinine clearance <30 ml min(-1) .

Oxypurinol, allopurinol and allopurinol-1-riboside in plasma following an acute overdose of allopurinol in a patient with advanced chronic kidney disease

Allopurinol is used to prevent gout. It is metabolized by xanthine oxidoreductase to oxypurinol, itself a xanthine oxidoreductase inhibitor, thereby reducing urate formation. It may also be metabolized by aldehyde oxidase to oxypurinol [1]. Another metabolite of allopurinol is allopurinol-1-riboside, formed directly by the enzyme purine nucleoside phosphorylase or indirectly through the dephosphorylation of allopurinol-1-ribotide [2]. An acute overdose of allopurinol can have contrasting outcomes. Severe reactions were reported in two cases [3], [4], while no reaction was reported in one case [5]. Allopurinol and oxypurinol are renally excreted, so renal impairment would reduce its clearance and possibly potentiate acute toxicity. However, the effect of renal impairment on clinical outcomes following an acute overdose has not been described. We report a case of allopurinol overdose in a patient with advanced chronic kidney disease. The case is of interest because accumulation of oxypurinol during routine dosing in renal failure has been considered a risk factor for severe allopurinol toxicity, including Stevens–Johnson syndrome and toxic epidermal necrolysis [6], which have mortalities of 30–50%. A 36-year-old transgender woman presented to hospital 30 min after ingesting 10 g allopurinol. The patient selected allopurinol because Internet information indicated low toxicity in overdose. There were no abnormal clinical signs on presentation and no adverse sequelae. She was discharged within 24 h. The medical history included an overdose of allopurinol 2 years earlier (oxypurinol concentration 44 mg l−1; time after allopurinol ingestion unknown), from which she also suffered no adverse effects. Her medical history also included gout (20 years), hypertension, hypercholesterolaemia and advanced chronic kidney disease [creatinine 493 µm; estimated glomerular filtration rate of 10–12 ml min−1 (1.73 m)−2] due to focal segmental glomerulosclerosis. The patient was reportedly taking allopurinol 100 mg day−1 prior to the overdose. Other medications included perindopril and rosuvastatin, as well as synthetic oestrogens. Urine screening was positive for opiates, benzodiazepines and amphetamines. She consented to return over the next week for additional blood tests. Allopurinol, oxypurinol and allopurinol-1-riboside concentrations were determined by high-performance liquid chromatography. The assay is validated for oxypurinol [7], and standard curves for all analytes were linear (r2 > 0.999). The identity and purity of each analyte was confirmed by comparison of retention times against standards and by scanning UV spectrophotometry of the peaks. Apparent elimination half-lives (t1/2) were estimated by nonlinear regression, assuming a one-compartment model. The t1/2 of oxypurinol was 65 h, considerably longer than found in healthy subjects (approximately 24 h) [1]. The longer t1/2 is attributed to the impaired renal function of this patient, as oxypurinol is renally excreted [1]. The peak plasma concentration (Cmax) of oxypurinol in this patient was 106 mg l−1. The apparent elimination t1/2 of allopurinol was 4.4 h. Again, this is longer than the t1/2 (1.2 ± 0.3 h) in healthy subjects [1], possibly due to saturation of xanthine oxidoreductase. The patients poor renal function may also have contributed to slower elimination, although renal clearance usually accounts for only approximately 10% of an oral dose of allopurinol [1]. The Cmax of allopurinol following a therapeutic dose of allopurinol (300 mg) is about 3 mg l−1,[1]. By contrast, the Cmax in this patient was much higher, at 29 mg l−1 (Figure 1). Figure 1 Time courses of allopurinol, oxypurinol and allopurinol-1-riboside after an overdose of allopurinol (10 g). Oxypurinol (); Allopurinol (); Allopurinol-1-riboside () Approximately 10% of allopurinol is excreted as allopurinol-1-riboside [1]. The t1/2 of the allopurinol-1- riboside is approximately 3 h following dosage of the riboside itself [8]. We found substantial concentrations of the riboside (up to 19 mg l−1). Given its high aqueous solubility, its renal excretion may be delayed in chronic kidney disease. One of the three previously reported cases of acute allopurinol overdose died from hepatic centrilobular necrosis. The dose of allopurinol was unknown, but the plasma concentration was recorded as 231 mg l−1, which is much greater than the value for our patient (29 mg l−1). The assay details were, however, not presented, and it is unclear whether oxypurinol or allopurinol was measured. Other causes of the hepatotoxicity may have been concurrent use of indomethacin and captopril [3]. Another patient who ingested 20 g allopurinol developed a variety of toxic effects, including hepatitis, leukopaenia, fever and diarrhoea but recovered with supportive care [4]. By contrast, in a third case, no adverse effects following the ingestion of approximately 20 g allopurinol were reported. The oxypurinol concentration for this latter subject was approximately 43 mg l−1 at approximately 12 h and the elimination half-life was 26 h [5]. By comparison, in our patient who purportedly took 10 g allopurinol, the estimated plasma concentration of oxypurinol at 12 h was approximately 100 mg l−1 (Figure 1). It is not known why there was no clinical toxicity. In the two cases where toxicity was reported, involvement of other drugs may have been contributory. The relationship between plasma concentrations of oxypurinol and adverse reactions is still unclear. Further investigation is required to clarify these observations. In summary, it is unclear whether or not adverse effects from acute overdoses of allopurinol are expected. Despite high concentrations of allopurinol and metabolites, our patient was largely unaffected by the overdose. Renal impairment appears to have contributed to the delayed elimination of allopurinol and its metabolites.

Could metformin be used in patients with advanced chronic kidney disease

To the Editor: We read with great interest the review article by Chowdhury et al. Over the last 5 years there has been great interest in relaxing the contraindication of renal impairment for prescribing metformin. We have examined the use of metformin in patients with advanced chronic kidney disease (CKD). Chowdhury et al. referenced our publication of a population pharmacokinetic model, which we used to simulate possible dosing regimens for patients with all grades of renal function (down to creatinine clearances of 15 mL/min). The goal of this analysis was to ensure that the 95th percentile peak plasma concentrations of metformin did not exceed 5 mg/L. These dosing regimens have been assessed by MedSafe (the New Zealand medicines regulatory agency) and have been incorporated into their metformin product label. We encourage other regulatory bodies to consider making similar changes. Metformin is largely eliminated unchanged by the kidneys and, consequently, a major concern is that patients with renal impairment will accumulate metformin and this could lead to the development of lactic acidosis, a serious adverse effect of metformin. A putative metformin plasma concentration of 5 mg/L has been suggested as being indicative of significant risk of metformin-associated lactic acidosis (MALA). We and others have suggested that metformin at therapeutic dosages is not a causative agent, even at concentrations >5 mg/L, but rather is an innocent by-stander. Many patients on metformin have comorbidities that increase the risk of lactic acidosis. Indeed, a recent retrospective study showed that, while metformin was significantly associated with an increased risk of the need for acute dialysis, this risk was conditional upon concomitant “patient frailty.” This implies that secondary characteristics that predispose a patient to enhanced lactate concentrations, such as age, renal function and cardiac failure, work in conjunction with metformin concentrations to induce damage. Our metformin dosing regimen in acute kidney injury has also been supported by Hung et al. Their study showed the adverse effects of “over-dosing” of metformin in the setting of advanced chronic kidney disease, showing that metformin increased all-cause mortality in a dose-dependent manner in patients with CKD stage 5. The design of novel formulations of metformin that reduce systemic exposure to metformin, such as a delayed release form absorbed from the distal small intestine, could further increase the safety of metformin in renally compromised patients. In addition to monitoring metformin plasma concentrations and renal function, a practice we and others encourage, we agree with the authors’ guidance on counselling patients with advanced CKD for “sick day rules.” One of the common signs patients reference prior to the onset of MALA is severe gastrointestinal symptoms (vomiting, diarrhoea). This should be a red-light warning for patients to cease metformin use and seek medical attention. Chowdhury et al. conclude that more studies examining the safety and efficacy of metformin in patients with advanced CKD are required. We have recently completed a small pharmacokinetic study on metformin in patients on chronic haemofiltration over 12 weeks. Furthermore, we propose to study metformin in a larger haemofiltration patient cohort, for a longer duration, our aim being to determine the optimum metformin dosing regimen required in this high-risk patient group (www.anzctr.org.au, ACTRN12616000675426). We, too, believe that the cardiovascular benefits associated with metformin use far outweigh the risks of MALA, particularly if the patients are monitored carefully.

The advent of interventional nephrology

Too many nephrologists have become intellectuals. Too content with the pleasures of office medicine and laboratory science. Too happy to refer patients to colleagues for services (ultrasound examinations, catheter placements, biopsies and so on) that could and should be performed in house. We are justifiably proud of our humanity and knowledge. Our patients, however, are probably more respectful of our nursing and surgical colleagues who do things to them. Our administrators are disdainful because all we do is think. It was not always so. The early nephrologists were practical people. They developed, along with interested engineers, the means of haemodialysis. The initial advances were achieved in peripheral hospitals. Somehow, over time, this interest was lost and the technical aspects of nephrology were surrendered to surgical and radiological colleagues. It is only recently that we have regained some control through the development of interventional nephrology. The most important treatment of kidney failure is haemodialysis. Peritoneal dialysis is effective in a minority of patients for a limited time. Transplantation is available for a minority of patients, albeit for a longer time. Haemodialysis is the only treatment that can be used for the great majority of patients, most of the time. Haemodialysis is best provided through veins draining an arteriovenous fistula. With good care, these veins remain useable for years. As Scribner has noted, ‘no other single development in the history of chronic haemodialysis has had a greater impact’. Repeated cannulation can damage the veins and thrombosis, haemorrhage and aneurysms can develop. Methods to correct these complications have become available, recently. The report by Mantha and colleagues is a good example of what can be achieved by practical nephrologists when they encounter dysfunctional fistulae. It is remarkable that a clinical success rate of over 90% was obtained. It is noteworthy that excellent results were obtained by physicians in a regional centre, much like the original developments all those years ago. What is the next step? We have a well-established method for the creation of an arteriovenous fistula. We have the means to correct thrombosis and aneurysm formation in the draining veins. We are left with a patient with a scar on their forearm. Perhaps the scar is not necessary. It should be possible, nowadays, to create a radiocephalic arteriovenous fistula using endoscopic and/or endovascular techniques. In 2016 we will celebrate the 50th anniversary of the report of Brescia and colleagues. We have 6 years to perfect our craft.