Variation in glucuronidation of lamotrigine in human liver microsomes

Abstract

1. Lamotrigine (LTG), a diaminotriazine anti-epileptic, is principally metabolized at the 2-position of the triazine ring to form a quaternary ammonium glucuronide (LTGG) by uridine glucuronosyl transferease (UGT) 1A3 and UGT1A4. It has been hypothesized that glucuronidation of anti-epileptic drugs is spared with age, despite a known decrease in liver mass, based on older studies with benzodiazepines such as lorazepam. To examine this, the formation rates of LTGG formation were measured by liquid chromatography-mass spectrometry (LC-MS) in a bank of human liver microsomes (HLMs) obtained from younger and elderly donors at therapeutic concentrations.

2. The formation rate of LTGG was not significantly different in HLMs obtained from younger and elderly subjects. A four- to five-fold variation for the formation of LTGG was observed within each microsomal bank obtained from elderly and younger donors, and the range of LTGG formation was observed to be 0.15–0.78 nmoles min⁻¹ mg⁻¹ of protein across the entire set of HLMs (n = 36, elderly and younger HLMs).

3. UGT1A4 and UGT1A3 catalysed the formation of LTGG with an intrinsic clearances of 0.28 and 0.02 μl min⁻¹ mg⁻¹ protein, respectively. UGT2B7 and UGT2B4 showed no measurable activity. No correlation was observed across the HLM bank for glucuronidation of LTG and valproic acid (a substrate for multiple UGT isoforms including UGT1A4).

Keywords::

• Uridine glucuronosyl transfereases (UGTs)
• glucuronidation
• lamotrigine
• anti-epileptic
• valproic acid

Acknowledgements

We thank Dr Timothy S Tracy for his guidance in preparation of the HLMs. We also thank Glaxo Inc. (GSK) for providing the LTGG reference standard. The assistance of Ms Bisi Abdul in carrying out microsomal incubations and that of Ms Falguni Gadkari in preparation of this manuscript is greatly appreciated.

Declaration of interest: The authors thank the National Institute of Health (NIH Grant NINDS P50 NS16308) for providing the financial support for this study.