Paracetamol, its metabolites and their transfer between maternal circulation and fetal brain in mono- and combination therapies

Abstract

Background: Paracetamol is one of the most commonly used medications. Due to its availability and perceived safety, its use is recommended even during pregnancy and for neonates. It is often combined with other drugs required for various chronic treatments. However, potential effects of drug interactions on paracetamol brain entry, especially in early development, are mostly unknown. Methods: Sprague Dawley rats at embryonic day E19, postnatal day P4, pregnant E19 dams and non-pregnant adult females were administered paracetamol (15 mg/kg) either as monotherapy or in combination with one of seven other drugs: cimetidine, digoxin, fluvoxamine, lamotrigine, lithium, olanzapine, valproate. Concentrations of parent paracetamol and its metabolites (paracetamol-glucuronide, paracetamol-glutathione and paracetamol-sulfate) in plasma, cerebrospinal fluid (CSF) and brain were measured by liquid chromatography and their entry into brain, CSF and transfer across the placenta were estimated. Results: In monotherapy, the concentration of parent paracetamol in plasma, CSF and brain remained similar and at all ages its brain entry was unrestricted. In combination therapies, its entry into CSF increased following co-treatment with olanzapine, but decreased in co-treatment with lamotrigine. Placental transfer of parent paracetamol remained unchanged with drug co-treatments, however transfer of paracetamol-sulfate increased with lamotrigine co-administration. Acutely administered paracetamol was more extensively metabolized in adults compared to younger ages resulting in increased concentration of its metabolites with age. Conclusions: Developmental changes in the apparent brain and CSF entry of paracetamol appear to be determined more by its metabolism, rather than by cellular control of its transfer across brain and placental barriers.