Mild acute renal failure potentiates metformin accumulation in the diabetic rat kidney without further impairment of renal function

To analyze, in acute renal failure (ARF) in diabetic rats, how moderate functional ARF would modify metformin (MET) pharmacokinetics and if plasma and renal tissue MET accumulation could aggravate renal insufficiency and/or elicit plasma lactate accumulation. Streptozotocin-induced diabetic rats were allocated to four groups: control, MET, ARF, ARF-MET (6–7 rats per group). MET (100 mg/kg/day) was given per os for two weeks before ARF was induced by drinking restriction and enalapril treatment. The effects of MET and/or ARF were examined in vivo on renal function in conscious rats (metabolic cages) and ex vivo on renal vascular reactivity (isolated kidney). MET treatment (plasma level: 5.3 ± 1.4 μg/ml, mean±SEM), resulted in biguanide accumulation in cortex and medulla (53 ± 17 and 80 ± 40 μg/g respectively). MET was devoid of any effect on creatinine clearance, mean blood pressure or renal vascular resistance, but moderately increased plasma lactate (3.8 ± 0.5 vs 3.2 ± 0.2 mM, P < 0.05) and decreased angiotensin II-induced renal vasoconstriction. ARF, although mild, decreased renal MET clearance (0.29 ± 0.05 vs 1.01 ± 0.31 ml/min/100 g, P < 0.05) and increased plasma and renal tissue MET levels (x 2–4). MET however did not worsen the fall in glomerular filtration rate, nor modify renal vascular reactivity. ARF did not change the MET-elicited moderate increase in plasma lactate. Despite the increase in MET plasma and renal tissue levels subsequent to moderate ARF, no harmful metabolic effect on plasma lactate and no further impairment of renal function was observed in MET-treated diabetic rats subjected to ARF. Une insuffisance rénale aiguë modérée potentialise l'accumulation de metformine dans le rein de rats diabétiques sans aggraver l'altération fonctionnelle rénale Analyser, chez des rats diabétiques soumis à une insuffisance rénale aiguë (IRA), comment une IRA fonctionnelle modérée peut modifier la pharmacocinétique de la metformine (MET), et évaluer si l'accumulation plasmatique et tissulaire rénale du biguanide peut aggraver une insuffisance rénale et/ou l'accumulation plasmatique de lactate. Des rats rendus diabétiques par une injection de streptozotocine, ont été répartis en quatre groupes: contrôle, MET, IRA, IRA-MET (6–7 rats par groupe). La MET (100 mg/kg/jour) a été administrée per os pendant 2 semaines avant l'induction d'une IRA par restriction hydrique et traitement par l'énalapril. Les effets de la MET et/ou de l'IRA ont été examinés in vi