Interaction Between Phenobarbital and Diphenylhydantoin in Animals and in Epileptic Patients*

Morselli, P. L.; Rizzo, Manfredi; Garattini, S.

doi:10.1111/j.1749-6632.1971.tb46892.x

Cited by 100 publications

(15 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although both CYP2C9 and 3A4 are regulated by PXR (7Y9), the induction of CYP2C9 in vivo in humans has only been shown for some of the strongest in vivo CYP3A inducers, e.g., phenobarbital and rifampicin (2,4). Furthermore, the fold induction for CYP2C9 probes in vivo is lower than for CYP3A probes.…”

Section: Discussionmentioning

confidence: 95%

Evaluation of Human Liver Slices and Reporter Gene Assays as Systems for Predicting the Cytochrome P450 Induction Potential of Drugs in Vivo in Humans

et al. 2006

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 95%

Evaluation of Human Liver Slices and Reporter Gene Assays as Systems for Predicting the Cytochrome P450 Induction Potential of Drugs in Vivo in Humans

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Competition takes place first, leading to an initial inhibition with a consequent rise in drug plasma concentrations. In most cases, inhibition remains the prevalent mechanism even during long term therapy, [63][64][65][66] probably because most patients are already metabolically induced and only limited further ind uction is possible. In most cases the modifications are modest and no dosage adjustment is needed, but the precise final effect cannot be anticipated [7.63,64,67-69] and must be determined on an individual basis, if necessary by plasma drug measurement.…”

Section: Phenytoin-phenobarbitalmentioning

confidence: 98%

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

“…An increase in phenobarbitone serum concentrations after addition of phenytoin has previously been documented in children. 5 Other workers have shown an increase in the phenobarbitone/primidone ratio in patients on phenytoin2 6 and have suggested that phenytoin induces the liver enzyme system responsible for the oxidation of primidone to phenobarbitone. Reynolds,7 however, proposed that the action of phenytoin was on phenobarbitone metabolism; our finding that the effect of phenytoin on phenobarbitone concentrations was at least as great in patients receiving phenobarbitone to that in patients receiving primidone supports a mechanism involving a direct action on phenobarbitone.…”

Section: Discusionmentioning

confidence: 99%

The effects of phenytoin on phenobarbitone and primidone metabolism.

Lambie¹,

Johnson²

1981

Journal of Neurology, Neurosurgery & Psychiatry

View full text Add to dashboard Cite

SUMMARY Serum concentrations of primidone and its metabolites-phenobarbitone and phenylethylmalonamide-were measured in 40 epileptic patients receiving treatment with primidone alone or primidone plus phenytoin. Serum phenobarbitone concentrations were also measured in 100 patients receiving phenobarbitone, alone or with phenytoin. Patients receiving either phenobarbitone or primidone in combination with phenytoin showed raised serum phenobarbitone concentrations. Phenytoin also caused raised phenylethylmalonamide concentrations in patients on primidone.Primidone is a desoxybarbiturate which is widely used in the treatment of epilepsy. It is converted in the body to two major metabolites-phenobarbitone and phenylethylmalonic acid (PEMA). Primidone exerts its anticonvulsant effect at least partly via oxidation to phenobarbitone. In addition, PEMA has been shown to have anticonvulsant activity in rats.' Since primidone is converted in vivo to these two active metabolites, whose anticonvulsant properties may differ, variations in the metabolism of the drug between different individuals are likely to be of therapeutic importance. Fincham et al2 found higher concentrations of phenobarbitone in patients receiving phenytoin and primidone, compared to patients on primidone only, and suggested that phenytoin induces primidone metabolism to phenobarbitone. However, in a previous study3 we found that an increase in the serum concentration of phenytoin caused an increase in the serum phenobarbitone concentration in patients receiving either phenobarbitone or primidone. This suggests that the action of phenytoin is directly on phenobarbitone rather than on metabolism of primidone.To establish the nature of the interaction between phenytoin and primidone we have carried out a study in epileptic patients of the effects of Address for reprint requests: Dr DG Lambie, Wellington Clinical

show abstract

Interaction Between Phenobarbital and Diphenylhydantoin in Animals and in Epileptic Patients*

Cited by 100 publications

References 38 publications

Evaluation of Human Liver Slices and Reporter Gene Assays as Systems for Predicting the Cytochrome P450 Induction Potential of Drugs in Vivo in Humans

Evaluation of Human Liver Slices and Reporter Gene Assays as Systems for Predicting the Cytochrome P450 Induction Potential of Drugs in Vivo in Humans

Pharmacokinetic Interactions Between Antiepileptic Drugs

The effects of phenytoin on phenobarbitone and primidone metabolism.

Contact Info

Product

Resources

About