title: Paracetamol decreases steady-state exposure to lamotrigine by induction of glucuronidation in healthy subjects.
abstract: OBJECTIVE
  Patients receiving lamotrigine therapy frequently use paracetamol concomitantly. While one study suggests a possible, clinically relevant drug-drug interaction, practical recommendations of the concomitant use are inconsistent. We performed a systematic pharmacokinetic study in healthy volunteers to quantify the effect of 4 day treatment with paracetamol on the metabolism of steady-state lamotrigine.
  
  
  METHODS
  Twelve healthy, male volunteers participated in an open label, sequential interaction study. Lamotrigine was titrated to steady-state (100 mg daily) over 36 days, and blood and urine sampling was performed in a non-randomized order with and without paracetamol (1 g four times daily). The primary endpoint was change in steady-state area under the plasma concentration-time curve of lamotrigine. Secondary endpoints were changes in total apparent oral clearance, renal clearance, trough concentration of lamotrigine and formation clearance of lamotrigine glucuronide conjugates.
  
  
  RESULTS
  Co-administration of lamotrigine and paracetamol decreased the steady-state area under the plasma concentration-time curve of lamotrigine by 20% (95% CI 10%, 25%; P < 0.001) from 166 to 127 μmol l(-1) . Concomitant administration of paracetamol increased the formation clearance of lamotrigine glucuronide conjugates by 45% (95% CI 18%, 79%, P = 0.005) from 1.7 to 2.8 l h(-1) , while the trough value of lamotrigine was reduced by 25% (95% CI 12%, 36%, P = 0.003) from 5.3 to 3.9 μmol l(-1) .
  
  
  CONCLUSIONS
  Paracetamol statistically significantly induced steady-state lamotrigine glucuronidation, resulting in a 20% decrease in total systemic exposure and a 25% decrease in trough value of lamotrigine. This interaction may be of clinical relevance in some patients.
authors.affiliation: Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gastrup
authors.affiliation: Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense.
authors.forename: Tore Bjerregaard
authors.initials: TB
authors.lastname: Stage
authors.affiliation: Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
authors.forename: Palle Bach Nielsen
authors.initials: PB
authors.lastname: Fruekilde
authors.affiliation: Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense.|Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Damkier
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D020719:Glucuronides / Q000378:metabolism*; D064368:Healthy Volunteers; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D008657:Metabolic Clearance Rate; D014018:Tissue Distribution; D014227:Triazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D000927:Anticonvulsants; D020719:Glucuronides; D014227:Triazines; D000082:Acetaminophen; D000077213:Lamotrigine
keywords: drug-related side effects; epilepsy; seizure; uridine diphosphate glucuronosyltransferase