Interaction of diphenylhydantoin (DPH) and tolbutamide in man

Wesseling, H; Mols-Thürkow, I.

doi:10.1007/bf00616418

Cited by 25 publications

(6 citation statements)

References 6 publications

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“…This would suggest that, although there is clear mutual in vitro metabolic inhibition of both drugs, the likelihood of significant in vivo inhibition and reduction in intrinsic clearance being observed at therapeutic dosages is small. This is supported by the work of Wesseling & Mols-Thurkow (1975) who showed that patients stabilised on phenytoin had a transient rise in unbound plasma phenytoin concentration and a persistent fall in total plasma phenytoin concentration when tolbutamide was coadministered for 2 days. These changes and the observations of Beech et al (1988) are explained by tolbutamide causing a displacement of phenytoin from plasma protein binding sites without alteration to the intrinsic clearance of phenytoin.…”

Section: Discussionmentioning

confidence: 70%

Relationship between phenytoin and tolbutamide hydroxylations in human liver microsomes.

Doecke

Veronese

Pond

et al. 1991

Brit J Clinical Pharma

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1 The metabolic interaction of phenytoin and tolbutamide in human liver microsomes was investigated.2 Phenytoin 4-hydroxylation (mean Km 29.6 ,zm, n = 3) was competitively inhibited by tolbutamide (mean Ki 106.2 ,wM, n = 3) and tolbutamide methylhydroxylation (mean Km 85.6 m,f n = 3) was competitively inhibited by phenytoin (mean Ki 22.6 jim, n = 3). 3 A significant correlation was obtained between phenytoin and tolbutamide hydroxylations in microsomes from 18 human livers (r, = 0.82, P < 0.001).4 Sulphaphenazole was a potent inhibitor of both phenytoin and tolbutamide hydroxylations with IC50 values of 0.4 ,Um and 0.6 ,UM, respectively.5 Mephenytoin was a poor inhibitor of both phenytoin and tolbutamide hydroxylations with IC50 values greater than 400 ,UM for both reactions. 6 Anti-rabbit P45011C3 IgG inhibited both phenytoin and tolbutamide hydroxylations in human liver microsomes by 62 and 68%, respectively. 7 These in vitro studies are consistent with phenytoin 4-hydroxylation and tolbutamide methylhydroxylation being catalysed by the same cytochrome P450 isozyme(s) in human liver microsomes.

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Section: Discussionmentioning

confidence: 70%

Relationship between phenytoin and tolbutamide hydroxylations in human liver microsomes.

Doecke

Veronese

Pond

et al. 1991

Brit J Clinical Pharma

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“…Concurrent administration of aluminium‐magnesium or calcium containing antacids (≥15 mls) and selected nasogastric or enteral tube feedings reduce the absorption of phenytoin ( Carter et al, 1981; Bauer, 1982). Valproic acid, tolbutamide, aspirin, and some other nonsteroidal antiinflammatory drugs displace phenytoin from albumin binding sites ( Wesseling & Mols‐Thurkow, 1975; Patsalos & Lascelles, 1977; Fraser et al, 1980; Monks & Richens, 1980; Dasgupta & Timmerman, 1996) resulting in a decrease in total drug concentrations, while the unbound concentration remains unchanged or may even increase when the displacing drug also inhibits phenytoin metabolism. Valproic acid, for example, is among the drugs that can inhibit the biotransformation of phenytoin resulting in an increase in serum unbound phenytoin concentration (Lai & Huang, 1993).…”

Section: Relevance Of Tdm For Individual Aedsmentioning

confidence: 99%

Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies

et al. 2008

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SUMMARYAlthough no randomized studies have demonstrated a positive impact of therapeutic drug monitoring (TDM) on clinical outcome in epilepsy, evidence from nonrandomized studies and everyday clinical experience does indicate that measuring serum concentrations of old and new generation antiepileptic drugs (AEDs) can have a valuable role in guiding patient management provided that concentrations are measured with a clear indication and are interpreted critically, taking into account the whole clinical context. Situations in which AED measurements are most likely to be of benefit include (1) when a person has attained the desired clinical outcome, to establish an individual therapeutic concentration which can be used at subsequent times to assess potential causes for a change in drug response; (2) as an aid in the diagnosis of clinical toxicity; (3) to assess compliance, particularly in patients with uncontrolled seizures or breakthrough seizures; (4) to guide dosage adjustment in situations associated with increased pharmacokinetic variability (e.g., children, the elderly, patients with associated diseases, drug formulation changes); (5) when a potentially important pharmacokinetic change is anticipated (e.g., in pregnancy, or when an interacting drug is added or removed); (6) to guide dose adjustments for AEDs with dose-dependent pharmacokinetics, particularly phenytoin.

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“…Other drugs which may displace phenytoin from its serum protein binding sites and thus produce a phenytoin profile as illustrated in figure 2 include amiodarone, azapropazone, diazoxide, salicylate, sulfafurazole, sulfamethoxypyridine and tolbutamide (Geaney et al 1983;Kurata & Wilkinson 1974;Leonard et al 1981;Lesko & Ruangtrakool 1987;Lunde et al 1970;Olanow et al 1981;Roe et al 1975;Wesseling & Mols-Thurkow 1975). Adjustment of phenytoin dosage will only be necessary if phenytoin metabolism is close to saturation and in particular if the displacement interaction is associated with simultaneous inhibition, as may occur with tolbutamide and amiodarone (Mc-Govern et al 1984;Tassaneeyakul et al 1992).…”

Section: Miscellaneous Interactionsmentioning

confidence: 99%

Antiepileptic Drugs

Patsalos

Duncan

1993

Drug Safety

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Approximately 20 to 30% of patients with active intractable epilepsy are commonly treated with polytherapy antiepileptic drug regimens, and these patients may experience complicated drug interactions. Furthermore, because of the long term nature of treatment, the possibility of drug interactions with drugs used for the treatment of concomitant disease is high. Classically, clinically significant drug interactions, both pharmacokinetic and pharmacodynamic, have been considered to be detrimental to the patient, necessitating dosage adjustment. However, this need not always be the case. With the introduction of new drugs (e.g. vigabatrin and lamotrigine) with known mechanisms of action, the possibility exists that these can be used synergistically. The most commonly observed clinically significant pharmacokinetic interactions can be attributed to interactions at the metabolic and serum protein binding levels. The best known examples relate to induction (e.g. phenobarbital, phenytoin, carbamazepine and primidone) or inhibition [e.g. valproic acid (sodium valproate)] of hepatic monoxygenase enzymes. The extent and direction of interactions between the different antiepileptic drugs are varied and unpredictable. Interactions in which the metabolism of phenobarbital, phenytoin or carbamazepine is inhibited are particularly important since these are commonly associated with toxicity. Some inhibitory drugs include macrolide antibiotics, chloramphenicol, cimetidine, isoniazid and numerous sulphonamides. A reduction in efficacy of antibiotic, cardiovascular, corticosteroid, oral anticoagulant and oral contraceptive drugs occurs during combination therapy with enzyme-inducing antiepileptic drugs. Discontinuation of the enzyme inducer or inhibitor will influence the concentrations of the remaining drug(s) and may necessitate dosage readjustment.

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Interaction of diphenylhydantoin (DPH) and tolbutamide in man

Cited by 25 publications

References 6 publications

Relationship between phenytoin and tolbutamide hydroxylations in human liver microsomes.

Relationship between phenytoin and tolbutamide hydroxylations in human liver microsomes.

Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies

Antiepileptic Drugs

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