Metabolism and excretion of the antiepileptic/antimigraine drug, topiramate in animals and humans

Abstract

The metabolism and excretion of 2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate (TOPAMAX, topiramate, TPM) have been investigated in animals and humans. Radiolabeled [14C] TPM was orally administered to mice, rats, rabbits, dogs and humans. Plasma, urine and fecal samples were collected and analyzed. TPM and a total of 12 metabolites were isolated and identified in these samples. Metabolites were formed by hydroxylation at the 7- or 8-methyl of an isopropylidene of TPM followed by rearrangement, hydroxylation at the 10-methyl of the other isopropylidene, hydrolysis at the 2,3-O-isopropylidene, hydrolysis at the 4,5-O-isopropylidene, cleavage at the sulfamate group, glucuronide conjugation and sulfate conjugation. A large percentage of unchanged TPM was recovered in animal and human urine. The most dominant metabolite of TPM in mice, male rats, rabbits and dogs appeared to be formed by the hydrolysis of the 2,3-O-isopropylidene group.

Topiramate as an add‐on antiepileptic drug in treating refractory canine idiopathic epilepsy

“…In pharmaconaive dogs, both unchanged TPM and its metabolites are eliminated mainly via renal excretion, and the degree of hepatic biotransformation is very low (Caldwell et al 2005). However, some have suggested that its rate of hepatic metabolism increases with concomitant PB medication (Gidal 2002).…”

Intravenous Topiramate: Pharmacokinetics in Dogs with Naturally Occurring Epilepsy

“…In our study, PB increased TPM clearance by 5.6-fold. To explain this discrepancy, Caldwell et al found that while 82% of TPM is excreted unchanged in the urine in humans, only 28% is excreted unchanged in dogs (29). PB is a known inducer of CYP 3A4, the major enzyme responsible for TPM metabolism.…”

Characteristics of selected second-generation antiepileptic drugs used in dogs

“…The results of Caldwell et al (2005) indicate that TPM is very poorly metabolized in dogs. They showed that a low percentage only of the total dosage of this agent was metabolized.…”

“…In phase I of the biotransformation there were three metabolites and in phase II of this process there were four glucuronide conjugates and two sulfate conjugates. Moreover, it was found that the most dominant pathway of metabolism of TPM in dogs was probably hydrolysis at the 2,2-o-isopropylidene group (Caldwell et al 2005). Caldwell et al (2005) found that topiramate was 96% eliminated in unchanged form.…”