Pharmacokinetic interaction between retigabine and lamotrigine in healthy subjects

Hermann, Róbert; Knebel, Norbert; Niebch, G.; Richards, Lyette S; Borlak, Jürgen; Locher, Mathias

doi:10.1007/s00228-003-0558-6

Cited by 53 publications

(45 citation statements)

References 20 publications

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“…In contrast, lamotrigine interacts with retigabine, which undergoes predominantly N-glucuronidation by UGT1A1, UGT1A3, UGT1A4, and UGT1A9, and its renal excretion (Hermann et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Hepatic UDP-Glucuronosyltransferase Is Responsible for Eslicarbazepine Glucuronidation

Loureiro¹,

Fernandes-Lopes²,

Bonifácio³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Eslicarbazepine acetate (ESL) is a once-daily novel antiepileptic drug approved in Europe for use as adjunctive therapy for refractory partial-onset seizures with or without secondary generalization. Metabolism of ESL consists primarily of hydrolysis to eslicarbazepine, which is then subject to glucuronidation followed by renal excretion. In this study, we have identified that human liver microsomes (HLM) enriched with uridine 5-diphosphoglucuronic acid give origin to a single Escherichia coli ␤-glucuronidase-sensitive eslicarbazepine glucuronide (most likely the O-glucuronide). The kinetics of eslicarbazepine glucuronidation in HLM was investigated in the presence and absence of bovine serum albumin (BSA). The apparent K m were 412.2 ؎ 63.8 and 349.7 ؎ 74.3 M in the presence and absence of BSA, respectively. Incubations with recombinant human UDP glucuronosyltransferases (UGTs) indicated that UGT1A4, UGT1A9, UGT2B4, UGT2B7, and UGT2B17 appear to be involved in eslicarbazepine conjugation. The UGT with the highest affinity for conjugation was UGT2B4 (K m ‫؍‬ 157.0 ؎ 31.2 and 28.7 ؎ 10.1 M, in the absence and presence of BSA, respectively). There was a significant correlation between eslicarbazepine glucuronidation and trifluoperazine glucuronidation, a typical UGT1A4 substrate; however, no correlation was found with typical substrates for UGT1A1 and UGT1A9. Diclofenac inhibited eslicarbazepine glucuronidation in HLM with an IC 50 value of 17 M. In conclusion, glucuronidation of eslicarbazepine results from the contribution of UGT1A4, UGT1A9, UGT2B4, UGT2B7, and UGT2B17, but the high-affinity component of the UGT2B4 isozyme may play a major role at therapeutic plasma concentrations of unbound eslicarbazepine.

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“…In contrast, lamotrigine interacts with retigabine, which undergoes predominantly N-glucuronidation by UGT1A1, UGT1A3, UGT1A4, and UGT1A9, and its renal excretion (Hermann et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Hepatic UDP-Glucuronosyltransferase Is Responsible for Eslicarbazepine Glucuronidation

Loureiro¹,

Fernandes-Lopes²,

Bonifácio³

et al. 2011

Drug Metab Dispos

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“…It significantly increases the plasma concentrations of clobazam in children with epilepsy (61) and inhibits the hydroxylation of its active metabolite norclobazam (19 (64). It increases the metabolism of lamotrigine (65). Phenytoin and carbamazepine increase the clearance of retigabine.…”

Section: Drug Interaction Profile Of New Versus Old Aedsmentioning

confidence: 99%

Innovations in Epilepsy Management – An Overview

Abraham

Shaju

2013

J Pharm Pharm Sci

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-In the past twenty years, thirteen new antiepileptic drugs (AEDs) have been introduced, each differing in their efficacy spectrum, mechanism of action, pharmacokinetics, safety and tolerability profiles. These newer AEDs symbolize a welcoming future in the management of epilepsy because they are able to produce a remarkable reduction in seizure frequency in up to 40% to 50% of the patients who had been refractory to old generation drugs. Despite the current availability of these new drugs, only a few patients with truly refractory seizures can be made seizure free. Although the newer agents are not superior to that of the older drugs, some have been shown to be non-inferior in terms of their efficacy. They offer additional advantages like better tolerability, ease of use, reduced interaction profile. Even though in most situations the older generation drugs still represent the best choice, advancing studies show that in many conditions, new generation drugs may be entirely vindicated for initial therapy. This urges a need for the search of novel and more efficacious new antiepileptic drugs in the management of uncontrollable seizures. More direct comparisons of newer versus newer and newer versus older drugs in clinical trials, both for monotherapy and adjunctive therapy must be conducted. More than 20 compounds with promising antiepileptic and neuroprotective properties have been discovered and are under various stages of drug development.

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“…22,28 RGB shows linear PK in adult healthy subjects up to 350 mg single and b.i.d. repeated oral doses.…”

Section: Introductionmentioning

confidence: 96%

“…RGB pharmacokinetics (PK) in healthy young subjects are characterized by rapid absorption (t max 1.6 h), a clearance of 0.58 l/h/kg, a volume of distribution of 6.2 l/kg, low plasma protein binding (about 80%), and terminal plasma half-life times of approximately 8.5 h. 27,28 Absolute bioavailability (F) of RGB oral immediate release dosage forms is about 60% (95% confidence interval (CI) 49-75%). 22,28 RGB shows linear PK in adult healthy subjects up to 350 mg single and b.i.d.…”

Section: Introductionmentioning

confidence: 99%

The role of Gilbert's syndrome and frequent NAT2 slow acetylation polymorphisms in the pharmacokinetics of retigabine

Hermann¹,

Borlak

Munzel

et al. 2006

Pharmacogenomics J

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Retigabine (RGB) is an investigational antiepileptic drug, which undergoes extensive UGT1A1, 1A9 and 1A4-mediated N-glucuronidation and Nacetylation. The mono-acetylated metabolite of RGB has some pharmacological activity and is denoted AWD21-360. We investigated whether the pharmacokinetics (PK) of RGB and AWD21-360 are altered in subjects with Gilbert's syndrome (GS) and/or with frequent N-acetyltransferase 2 (NAT2) slow acetylator (SA) polymorphisms. Based on consistent genotyping and phenotyping screening results, 37 Caucasian subjects (21-46 years; 31 men, six women) were assigned to one of the following groups:. Subjects received single and multiple (b.i.d.) 200-mg oral RGB doses over 5 days. Blood samples were collected up to 60 h after dosing for plasma PK of RGB and AWD21-360. Group comparisons were performed by ANOVA. Single-dose PK of RGB and AWD21-360 and multipledose PK of RGB did not differ significantly between groups. After multiple dose treatment, RA subjects showed a significantly higher total exposure to AWD21-360 of about 32% (95% CI 101.9-172.5) relative to SA subjects (P ¼ 0.0362). The UGT1A1 metabolic capacity (i.e. presence or absence of GS), however, did not significantly affect the overall exposure to AWD21-360. The results indicate that the PK of RGB is unaltered in individuals with GS, in subjects with NAT2 SA status, and in carriers of both variants, whereas the total exposure to AWD21-360 is significantly related to the RA or SA status of subjects. Results further suggest that metabolic switching to the mono-acetylated metabolite AWD21-360 may partially compensate for the impaired glucuronidation capacity in GS subjects. RGB treatment showed no significant differences in tolerability and safety between groups.

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Pharmacokinetic interaction between retigabine and lamotrigine in healthy subjects

Cited by 53 publications

References 20 publications

Hepatic UDP-Glucuronosyltransferase Is Responsible for Eslicarbazepine Glucuronidation

Hepatic UDP-Glucuronosyltransferase Is Responsible for Eslicarbazepine Glucuronidation

Innovations in Epilepsy Management – An Overview

The role of Gilbert's syndrome and frequent NAT2 slow acetylation polymorphisms in the pharmacokinetics of retigabine

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