Abstract

Urinary excretion of a variety of quaternary ammonium glucuronides has been generally reported to be confined to humans and some monkeys. Lower animal species appear to lack or have limited ability to form these unusual metabolites. In this report, the excretion of the quaternary ammonium glucuronide of lamotrigine, an investigational 1,2,4-triazine anticonvulsant, in guinea pigs is described. Lamotrigine 2-N-glucuronide accounted for 60% of an i.v. bolus dose of lamotrigine in guinea pig urine. Less than 6% of the dose was excreted unchanged. The pharmacokinetics of lamotrigine after an iv bolus dose of 10 mg/kg were determined with an ion-pairing, reversed-phase HPLC assay. Lamotrigine is a low clearance drug (Cl = 2.51 +/- 0.063 ml/min/kg) with a large volume of distribution (Vss = 2.23 +/- 0.403 liter/kg). The half-life of lamotrigine was 11.5 +/- 2.0 hr. The elimination of the glucuronide was formation rate-limited and it was excreted by extensive tubular secretion. The glucuronide was also formed in Triton-X-100-activated liver microsomes and isolated guinea pig hepatocytes. The KM was 2.10 +/- 0.44 mM and the Vmax was 0.252 +/- 0.0312 nmol/min/mg protein in untreated microsomes. Pretreatment with beta-naphthoflavone did not induce lamotrigine glucuronidation. In hepatocytes, production of the glucuronide was linear for 60 min after a short lag period and 2 mM lamotrigine was not cytotoxic. Lamotrigine is only the second example of a compound that is primarily metabolized to a quaternary ammonium glucuronide in a lower animal species.