Carbamazepine-10,11-diol Steady-State Serum Levels and Renal Excretion During Carbamazepine Therapy in Adults and Children

Bourgeois, Blaise F. D.; Wad, Nils

doi:10.1097/00007691-198409000-00001

Cited by 44 publications

(37 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The autoinduction process can be estimated to increase CBZ clearance from an average of 0.61 (total absence of autoinduction) to 1.59 L/kg/day (full autoinduction), which is a 2.61-fold increase in enzymatic activity. The value of 1.59 Llkgiday for clearance of CBZ with chronic monotherapy is in good agreement with the value of 1.67 L/kg/day previously calculated from steady-state serum levels (Bourgeois and Wad, 1984). Autoinduction of CBZ primarily induces the components of the microsomal monooxygenase system (Faigle and Feldmann, 1989).…”

Section: Discussionsupporting

confidence: 86%

Rapid Reversibility of Autoinduction of Carbamazepine Metabolism After Temporary Discontinuation

1994

Self Cite

View full text Add to dashboard Cite

Patients in whom carbamazepine (CBZ) monotherapy is discontinued for preoperative EEG/video monitoring often display toxicity if their previous maintenance dosage is resumed, even after a few days without CBZ. To determine whether this is due to rapid reversibility of autoinduction of CBZ metabolism, single-dose studies of CBZ pharmacokinetics were performed before and after discontinuation for monitoring in 6 adults receiving CBZ monotherapy. The CBZ-free period was 5.7 +/- 1.1 days (mean +/- SD). The pharmacokinetic parameters of CBZ before and after discontinuation were volume of distribution (Vd) 1.28 +/- 0.29 versus 1.22 +/- 0.331/kg (NS), elimination half-life (t1/2) 13.7 +/- 1.67 versus 22.2 +/- 2.36 h (p < 0.001), and clearance (Cl) 1.54 +/- 0.39 versus 0.92 +/- 0.32 L/kg/day (p = 0.012). Assuming that deinduction is a first-order process, a deinduction t1/2 of 3.84 days was obtained by log linear regression analysis. We showed that after CBZ discontinuation half of the enzymatic autoinduction is already lost after 3.84 days, indicating very rapid deinduction. Our results also provide the necessary information to predict clearance and appropriate dosage reduction for CBZ at time of reintroduction.

show abstract

Section: Discussionsupporting

confidence: 86%

Rapid Reversibility of Autoinduction of Carbamazepine Metabolism After Temporary Discontinuation

1994

Self Cite

View full text Add to dashboard Cite

show abstract

“…The ratio of steady state plasma CBZ-diol to plasma CBZ concentration has previously been used as an indicator of the induction of CBZ metabolism (Bourgeois and Wad 1984;Tomson et al 1989). For practical purposes, virtual steady state conditions applied for CBZ plasma concentrations from 6 to 32 h after each intake of the drug in the present study.…”

Section: Discussionmentioning

confidence: 99%

Early stage autoinduction of carbamazepine metabolism in humans

Bernus

Dickinson

Hooper

et al. 1994

Eur J Clin Pharmacol

View full text Add to dashboard Cite

Six healthy young adult male volunteers were given two 600 mg (2540 mu moles) oral doses of carbamazepine (CBZ) 5 days apart. Serial concentrations of CBZ and its 10,11-epoxy (CBZ-epoxide) and 10,11-dihydro-10,11-trans-dihydroxy (CBZ-diol) metabolites in plasma, and daily excretions of these substances and the 2-hydroxy (2-OH-CBZ), 3-hydroxy (3-OH-CBZ) and 9-hydroxymethyl-10-carbamoylacridan (acridan) metabolites in urine were followed for 5 days after each dose. Pharmacokinetic analysis showed that autoinduction of CBZ metabolism was present within 6-10 days of the initial drug dose. The mean oral clearance of CBZ increased from 1.48 to 1.74 l.h-1 (difference 0.26 l.h-1, 95% confidence interval 0.11 to 0.41 l.h-1) and the mean percentage urinary recovery of the amount of CBZ eliminated increased from 41.8% to 44.6% (difference 2.8%, 95% confidence interval 0.5 to 5%) between the two studies 5 days apart. The data for daily clearance to metabolite and the time-courses of the plasma CBZ-epoxide to CBZ and CBZ-diol to CBZ concentration ratios suggested that autoinduction had begun by the second day after CBZ intake, and involved not only the epoxide-diol pathway but, to a lesser extent, the oxidations to phenolic derivatives.

show abstract

“…On the contrary, phenobarbital significantly increases the clearance of carbamazepine and carbamazepine 1O,1l_epoxide. [70][71][72]74,[81][82][83][129][130][131][132][133] The effect is more pronounced on epoxidation, [134,135] yielding a relative increase in metabolite concentrations (from about 15% before the interaction to about 40% ) [73.79-84,130,136,137] with a possible matched increase in contribution to the overall clinical effects. In practice, steady-state plasma carbamazepine concentrations may be halved and those of carbamazepine 10,1l-epoxide may be unchanged after phenobarbital is introduced.…”

Section: 5 Phenobarbital-carbamazepinementioning

confidence: 99%

Pharmacokinetic Interactions Between Antiepileptic Drugs

Riva¹,

Albani²,

Contin³

et al. 1996

Clinical Pharmacokinetics

151

View full text Add to dashboard Cite

Antiepileptic drug interactions represent a common clinical problem which has been compounded by the introduction of many new compounds in recent years. Most pharmacokinetic interactions involve the modification of drug metabolism; the propensity of antiepileptic drugs to interact depends on their metabolic characteristics and action on drug metabolic enzymes. Phenobarbital, phenytoin, primidone and carbamazepine are potent inducers of cytochrome P450 (CYP), epoxide hydrolase and uridine diphosphate glucuronosyltransferase (UDPGT) enzyme systems; oxcarbazepine is a weak inducer of CYP enzymes, probably acting on a few specific isoforms only. All stimulate the rate of metabolism and the clearance of the drugs which are catabolised by the induced enzymes. Valproic acid (valproate sodium) inhibits to different extents many hepatic enzyme system activities involved in drug metabolism and is able to significantly displace drugs from plasma albumin. Felbamate is an inhibitor of some specific CYP isoforms and mitochondrial beta-oxidation, whereas it is a weak inducer of other enzyme systems. Topiramate is an inducer of specific CYP isoforms and an inhibitor of other isoforms. Ethosuximide, vigabatrin, lamotrigine, gabapentin and possibly zonisamide and tiagabine have no significant effect on hepatic drug metabolism. Apart from vigabatrin and gabapentin, which are mainly eliminated unchanged by the renal route, all other antiepileptic drugs are metabolised wholly or in part by hepatic enzymes and their disposition may be altered by metabolic changes. Some interactions are clinically unremarkable and some need only careful clinical monitoring, but others require prompt dosage adjustment. From a practical point of view, if valproic acid is added to lamotrigine or phenobarbital therapy, or if felbamate is added to phenobarbital, phenytoin or valproic acid therapy, a significant rise in plasma concentrations of the first drug is expected with a corresponding increase in clinical effects. In these cases a concomitant reduction of the dosage of the first drug is recommended to avoid toxicity. Conversely, if a strong inducer is added to carbamazepine, lamotrigine, valproic acid or ethosuximide monotherapy, a significant decrease in their plasma concentrations is expected within days or weeks, with a possible reduction in efficacy. In these cases a dosage increase of the first drug may be required.

show abstract

Carbamazepine-10,11-diol Steady-State Serum Levels and Renal Excretion During Carbamazepine Therapy in Adults and Children

Cited by 44 publications

References 0 publications

Rapid Reversibility of Autoinduction of Carbamazepine Metabolism After Temporary Discontinuation

Rapid Reversibility of Autoinduction of Carbamazepine Metabolism After Temporary Discontinuation

Early stage autoinduction of carbamazepine metabolism in humans

Pharmacokinetic Interactions Between Antiepileptic Drugs

Contact Info

Product

Resources

About