Metabolic acidosis with a high anion: A drug-drug interaction between paracetamol and flucloxacillin

Background: Five-oxoproline is a product of disordered glutathione metabolism in the gamma glutamyl cycle: glutathione deficiency removes the feedback inhibition resulting in the formation of γ -glutamylcysteine and elevated concentrations of γ -glutamylcysteine leading to the formation of 5-oxoproline, which is degraded by 5-oxoprolinase. Both paracetamol and flucloxacillin interact with the gamma glutamyl cyclus. Paracetamol depletes glutathione which leads to the accumulation of γ -glutamylcysteine that is a precursor for 5-oxoproline and flucloxacillin inhibits 5-oxoprolinase which also leads to accumulation of 5-oxoproline. The accumulation of 5-oxoproline, an acid residue, may lead to a high anion gap and a metabolic acidosis. Although a few cases of this drug-drug interaction are published, it is still not included in the summary of product characteristics of paracetamol and flucloxacillin or included in medication safety monitoring systems in hospitals and pharmacies. Material and Methods: We analyzed all submitted reports to the Netherlands' Pharmacovigilance Centre Lareb till 31 December 2014 on this drug-drug interaction. Results: Lareb received 3 reports of metabolic acidosis where both paracetamol and flucloxacillin, used in therapeutic doses, were marked as suspected and interacting drugs. The cases concern 3 females of older age (67, 72 and 78 years). The aberrant mechanism of the 72 year old female was treated with acetyl cysteine; she died. The other 2 women were treated with sodium bicarbonate and recovered. We could not confirm a relationship between the treatment and the outcome of the interaction. Conclusions: Our reported cases contribute to the suspicion of a relationship between metabolic acidosis and concomitantly used paracetamol and flucloxacillin. This drug interaction should be included in the summary of drug characteristics and included in medication monitoring systems in health institutions