PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of brjclinpharmLink to Publisher's site
 
Br J Clin Pharmacol. 2016 April; 81(4): 735–741.
Published online 2016 January 25. doi:  10.1111/bcp.12840
PMCID: PMC4799936

Paracetamol decreases steady‐state exposure to lamotrigine by induction of glucuronidation in healthy subjects

Abstract

Aim

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.

Conclusion

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.

Keywords: drug‐related side effects, epilepsy, seizure, uridine diphosphate glucuronosyltransferase

Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society