Effects of charcoal on the absorption and elimination of the antiepileptic drugs lamotrigine and oxcarbazepine

Abstract

Objective:

The effects of single and repeated doses of oral activated charcoal (OAC) on the absorption and elimination of the antiepileptic drugs, lamotrigine (CAS 84057-84-1, LTG, Lamictal™) and oxcarbazepine (CAS 28721-07-5, OXC, Trileptal™) were studied in healthy volunteers to assess the therapeutic potential of OAC in the treatment of LTG and OXC overdose.

Methods:

In three open, randomized, cross-over sessions with ≥14 days wash-out, LTG 100 mg and OXC 600 mg were given orally, each to 6 subjects. In one session the drugs were given alone, and in two others with single (50 g) or repeated (20 g) doses of OAC as water suspension. The single OAC dose was given 30 min after the drugs, and repeated doses 6–72 h after LTG and 12–48 h after OXC. Serumconcentrations of the parent drugs as well as those of the pharmacolocigally active metabolite of OXC, 10,11-dihydro-10-hydroxy-carbamazepine (MHD), were measured with reverse-phase highper-formance liquid chromatography. Pharmacokinetic variables were calculated by non-compartmental analysis.

Results:

Single OAC dose decreased AUC_0–∞ of LTG, OXC and MHD to 58%, 2.8% and 4.2% of the respective variables without OAC. Also T _max of OXC and MHD decreased to 4.4% and 8.1%, respectively. Repeated OAC doses after LTG decreased its AUC from 6 h to infinity (AUC_6–∞) to 39% and t_1/2β to 44%. Repeated OAC doses after a single dose of OXC decreased the AUC_12–∞ and t_1/2β of MHD to 46% and 45% of the respective variables without OAC.

Conclusion:

OAC greatly reduces gastrointestinal absorption of LTG and especially that of OXC, and it accelerates the elimination of LTG and MHD. The use of OAC is hence strongly favoured in the treatment of overdose with these drugs.

Key words

Antiepileptic drugs - CAS 28721-07-5 - CAS 84057-84-1 - Lamotrigine, overdose, pharmacokinetics - Oral activated charcoal - Oxcarbazepine, overdose, pharmacokinetics

• References

• 1 Ettinger AB, Argoff CE. Use of antiepileptic drugs for non-epileptic conditions: psychiatric disorders and chronic pain. Neurotherapeutics. 2007; 4: 75-83
• 2 Cohen AF, Land GS, Breimer DD, Yuen WC, Winton C, Peck AW. Lamotrigine, a new anticonvulsant: pharmacokinetics in normal humans. Clin Pharmacol Ther. 1987; 42: 535-41
• 3 Bourgeois BFD. Pharmacokinetic properties of current antiepileptic drugs: whatimprovementsare needed. Neurology. 2000; 55 (3) S11-6
• 4 Chan V, Morris RG, Ilett KF, Tett SE. Population pharmacokinetics of lamotrigine. Ther Drug Monit. 2001; 23: 630-5
• 5 Dickinson RG, Hooper WD, Dunstan PR, Eadie MJ. First dose and steady-state pharmacokinetics of oxcarbazepine and its 10-hydroxy metabolite. Eur J Clin Pharmacol. 1989; 37: 69-74
• 6 May TW, Korn-Merker E, Rambeck B. Clinical pharmacokinetics of oxcarbazepine. Clin Pharmacokinet. 2003; 42: 1023-42
• 7 Kristensen O, Klitgaard NA, Jonsson B, Sindrup S. Pharmacokinetics of 10-OH-carbazepine, the mean metabolite of the antiepileptic oxcarbazepine, from serum and saliva concentrations. Acta Neurol Scand. 1983; 68: 145-50
• 8 Lloyd P, Flesch G, Dieterle W. Clinical pharmacology and pharmacokinetics of oxcarbazepine. Epilepsia. 1994; 35 (3) S10-3
• 9 Sbei M, Campellone JV. Stupor from lamotrigine toxicity. Epilepsia. 2001; 42: 1082-3
• 10 Lofton AL, Klein-Schwartz W. Evaluation of lamotrigine toxicity reported to poison centers. Ann Pharmacother. 2004; 38: 1811-5
• 11 Dinnerstein E, Jobts BC, Williamson PD. Lamotrigine intoxication provoking status epilepticus in an adult with localization related epilepsy. Arch Neurol. 2007; 64: 1344-6
• 12 Reimers A, Reinholt G. Acute lamotrigine overdose in anadolelescent. Ther Drug Monit. 2007; 29: 669-70
• 13 Van JMOpstal, Janknegt R, Cilissen J, L’Ortije WH, Nel WH, De FHeer. Severe overdosage with the antiepileptic drug oxcarbazepine. Br J Clin Pharmacol. 2004; 58: 329-31
• 14 Furlanut M, Franceschi L, Poz D, Silvestri L, Pecorari M. Acute oxcarbazepine, benazepril, and hydrochlorothiazide overdose with alcohol. Ther Drug Monit. 2006; 28: 267-8
• 15 Neuvonen PJ. Clinical pharmacokinetics of oral activated charcoal in acute intoxications. Clin Pharmacokinet. 1982; 7: 465-89
• 16 Neuvonen PJ, Olkkola KT. Oral activated charcoal in the treatment of intoxications: role of single and repeated doses. Med Toxicol Adverse Drug Exp. 1988; 3: 33-58
• 17 Montoya-Cabrera MA, Sauceda-Garcia JM, Escalante-Galindo P, Flores-Alvarez E, Ruiz-Gomez A. Carbamazepine poisoning in adolescent suicide attempters: effectiveness of multiple-dose activated charcoal in enhancing carbamazepine elimination. Arch Med Res. 1996; 27: 485-9
• 18 Brahmi N, Kouraichi N, Thabet H, Amamou M. Influence of activated charcoal on the pharmacokinetics and the clinical features of carbamazepine poisoning. Am J Emerg Med. 2006; 24: 440-3
• 19 Hiller A, Nguyen N, Strassburg CP, Li Q, Jainta H, Pechstein B et al Retigabine Nglucuronidation and its potential role in the enterohepatic circulation. Drug Metab Dispos. 1999; 27: 605-12
• 20 Menge GP, Dubois JP, Bauer G. Simultaneous determination of carbamazepine, oxcarbazepine and their main metabolites in plasma by liquid chromatography. J Chromatogr. 1987; 414: 477-83
• 21 Fraser AD, MacNeil W, Isner AF, Camfield PR. Lamotrigine analysis in serum by highperformance liquid chromatography. Ther Drug Monit. 1995; 17: 174-8
• 22 Briassoulis G, Kalabalikis P, Tamiolaki M, Hatzis T. Lamotrigine childhood overdose. Pediatr Neurol. 1998; 19: 239-42
• 23 Barker MJ, Benitez JG, Temullo S, Juhi GA. Acute oxcarbazepine and atomoxetine overdose with quetiapine. Vet Hum Toxicol. 2004; 46: 130-2
• 24 Zidd AG, Hack JB. Pediatric ingestion of lamotrigine. Pediatr Neurol. 2004; 31: 71-2
• 25 Olkkola KT, Neuvonen PJ. Treatment of intoxications using single and repeated doses of oral activated charcoal. J Toxicol Clin Exp. 1989; 9: 265-75
• 26 Alaspää AO, Kuisma MJ, Hoppu K, Neuvonen PJ. Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med. 2005; 45: 207-12