Flucloxacillin instantly decreases serum levels of valproic acid: A case report

Valproic acid (VPA) is used for epilepsy and bipolar disorder. It has near-complete bioavailability and is primarily metabolized by glucuronosyltransferases and mitochondrial oxidation. This case highlights a 79-year-old male with bipolar disorder on VPA therapy that started with flucloxacillin for Staphylococcus aureus bacteraemia and exhibited significantly reduced VPA serum levels. During hospitalization, flucloxacillin treatment correlated with a sharp decline of 75% in VPA total serum levels, a novel drug–drug interaction not previously reported. Nonadherence and absorption issues of VPA were ruled out, confirming flucloxacillin's role in reducing VPA levels. Because free-fraction serum levels of VPA remained within therapeutic range (5–25 mg/L) and our patient's bipolar disorder remained stable at 1000 mg twice daily, a dose increase was not necessary. Previous reports described cytochrome P450 enzyme induction as the mechanism of flucloxacillin lowering serum levels of immunosuppressants and antimycotics. Because only 10% of VPA is metabolized by cytochrome P450 enzymes, this is not plausible for this case. The proposed mechanism for the VPA–flucloxacillin drug–drug interaction is flucloxacillin as inducer of glucuronosyltransferase enzymes via the pregnane X receptor pathway, accelerating VPA metabolism. Because this case showed that free-fraction serum levels remained within therapeutic range, it underscores the need for free-fraction VPA monitoring in bipolar disorder and flucloxacillin therapy. When VPA is used for epilepsy, it is advised to consider alternative antibiotics to avoid this interaction.