Lamotrigine glucuronidation

Lamotrigine is metabolized by glucuronidation, possibly by the UGT 1A4 system. As such, it is vulnerable to other UGT inducers—oral contraceptives, phenytoin, carbamazepine, phenobarbital and primidone, and to a UGT inhibitor, valproate (Hachad et ah, 2002). 

Induction of the glucuronidation of several drugs, including lamotrigine by oral contraceptive steroids (OCSs), has been observed (134). The formation clearance to the acyl glucuronide of diflunisal increased from 3.01 mL/min in... 

Remmel RP, Sinz MW. A quaternary ammonium glucuronide is the major metabolite of lamotrigine in guinea pigs. In vitro and in vivo studies. Drug Metab Disp 1991 19(3) 630-636. 

Plasma concentrations of lamotrigine were reduced in seven women taking an oral contraceptive (mean reduction 49%, range 41-64%), probably through induction of glucuronide conjugating enzymes (77). 

Rifampicin induced the glucuronidation of lamotrigine, increasing total clearance about two-fold. 

Figure 21 Examples of unusual glucuronidation reactions lamotrigine (quaternary ammonium glucuronide) and sulfinpyrazone (carbon-linked glucuronide). ...

J Magdalou, R Herber, R Bidfault, G Siest. In vitro N-glucuronidation of a novel antiepileptic drug, lamotrigine, by human liver microsomes. J Pharm Exp Ther 260 1166, 1992. 

MW Sinz, RP Remmel. Isolation and characterization of a novel quaternary ammonium-linked glucuronide of lamotrigine. Drug Metab Dispos 19 149, 1991. 

PHARMACOKINETICS Zonisamide is almost completely absorbed after oral administration, has a long tj, ( 63 hours), and is -40% bound to plasma protein. Approximately 85% of an oral dose is excreted in the urine, principally as unmetaboUzed zonisamide and a glucuronide of the CYP3A4 metabolite, sulfamoylacetyl phenol. Phenobarbital, phenytoin, and carbamazepine decrease the plasma concentration/dose ratio of zonisamide, whereas lamotrigine increases this ratio. Zonisamide has Uftle effect on the plasma concentrations of other antiseizure drugs. 

Carboxyl group clofibrate, ciprofibrate, etodolac, fenoprofen, ibuprofen, ketoprofen, naproxen (racemic > 5), valproic acid and formation of simvastatin and atorvastatin lactones via an intermediate acyl glucuronide Tertiary amines amitriptyline, chlorpheniramine, chlorpromazine, clozapine, cyproheptadine, diphenylamine, doxepin, imipramine, ketotifen, loxapine, promethazine, tripellenamine, trifluoperazine Aromatic heterocyclic amines croconazole, lamotrigine, nicotine (30X velocity than UGT1A3), 1-phenylimidazole, posaconazole, retigabine Primary and secondary amines ... 

The apparent contradiction between the results described is not understood. One suggestion to account for the toxic symptoms seen in some patients is that it occurs at the site of action (a pharmacodynamic interaction) rather than because lamotrigine increases the carbamazepine-10,11-epoxide serum levels. Carbamazepine may induce the glucuronidation of lamotrigine. 

Rifampicin increases the loss of lamotrigine from the body, probably by inducing glucuronidation via UDP-glucuronyl transferases. It was suggested that isoniazid may have inhibited lamotrigine metabolism. ... 

Lopinavir/ritonavir probably decreases lamotrigine levels by induction of glucuronidation (suggested by the increase in the AUC ratio of lamotrigine 2N-glucuronide to lamotrigine). 

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