Assay of the major (4-hydroxylated) metabolites of diphenylhydantoin in human urine

Karlén, B; Garle, Mats; Rane, Anders; Gutová, M; Lindborg, B.

doi:10.1007/bf00562663

Cited by 17 publications

(3 citation statements)

References 11 publications

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“…Some values were fairly high compared to most published recovery data, such as in the review by Woodbury and Swinyard,28 but were in close agreement with the data by Karlen et aI. 14 Since transformation into this metabolite is dose-dependent, this may be explained by the low dose we used. 28 As already reported, plasma concentration levels of OPH at steady 27 In the uremic patients, the 86% decrease in renal clearance of the unconjugated metabolite did not produce the expected sixfold increase in the plasma levels.…”

Section: Discussionsupporting

confidence: 90%

Plasma levels and renal excretion of phenytoin and its metabolites in patients with renal failure

Borgå¹,

Hoppel²,

Odar‐Cederlöf³

et al. 1979

Clinical Pharmacology &Amp; Therapeutics

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Phenytoin (DPH) and its two major metabolites, conjugated and unconjugated 5-(4-hydroxyphenyl)-5-phenylhydantoin (4-OH-DPH), have been studied in plasma and urine to 4 healthy subjects and 3 uremic patients during two weeks on DPH, 0.1 gm daily. Only 0.4% to 1.2% of the dose was excreted as unchanged DPH. The DPH concentrations in urine were in the same range as calculated unbound levels of DPH in plasma in the normal subjects; 1% to 2% of the dose was excreted as unconjugated 4-OH-DPH in the normal subjects. In the uremic patients, renal clearance of this metabolite was reduced to one-sixth that percentage. Plasma concentrations rose to values twice as high as normal, indicating increased rate of glucuronidation. Urinary recovery of conjugated 4-OH-DPH in healthy subjects was 52% to 94%. Its renal clearance was close to glomerular filtration rate when corrected for protein binding, suggesting elimination by glomerular filtration rate when corrected for protein binding, suggesting elimination by glomerular filtration only. Plasma concentrations of conjugated 4-OH-DPH reached plateau levels around day 4 in normal subjects. In the uremic patients, plasma concentrations of this metabolite accumulated to levels 10 times normal, and after 15 days of medication plateau levels did not seem to have been reached.

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Section: Discussionsupporting

confidence: 90%

Plasma levels and renal excretion of phenytoin and its metabolites in patients with renal failure

Borgå¹,

Hoppel²,

Odar‐Cederlöf³

et al. 1979

Clinical Pharmacology &Amp; Therapeutics

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“…Less than 5% of the daily dose of phenytoin is excreted unchanged in the urine (Bochner et al, 1973;Karlen et al, 1975). About 70-80% is eliminated as p-HPPH, mainly in the conjugated form.…”

Section: Measurement Of Urinary P-hpph:dph Ratiomentioning

confidence: 99%

Interaction between vigabatrin and phenytoin.

Rimmer

Richens

1989

Brit J Clinical Pharma

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1. The study was designed to determine the mechanism by which vigabatrin causes a fall in plasma phenytoin concentrations when added to the drug therapy of eight epileptic patients. 2. Total plasma phenytoin concentration was measured before and at intervals during 5 weeks' treatment with vigabatrin. 3. Plasma protein binding of phenytoin, the urinary ratio of phenytoin to 5‐(p‐hydroxyphenyl)‐5‐ phenylhydantoin, and antipyrine clearance were measured before and at the end of treatment period. 4. Mean plasma phenytoin concentration fell significantly by 23% during the fifth week. 5. No change was found in any of the other measures. 6. Although an interaction between phenytoin and vigabatrin has been confirmed, the mechanism has not been elucidated.

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“…It is approximately 90% bound to serum proteins and is metabolised in the liver to numerous metabolites, with 5-(4-hydroxyphenyl)-5-(phenylhydantoin) being by far the most prevalent (approximately 80% of total; Karlen et al 1975). It is approximately 90% bound to serum proteins and is metabolised in the liver to numerous metabolites, with 5-(4-hydroxyphenyl)-5-(phenylhydantoin) being by far the most prevalent (approximately 80% of total; Karlen et al 1975).…”

Section: Phenytoinmentioning

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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Assay of the major (4-hydroxylated) metabolites of diphenylhydantoin in human urine

Cited by 17 publications

References 11 publications

Plasma levels and renal excretion of phenytoin and its metabolites in patients with renal failure

Plasma levels and renal excretion of phenytoin and its metabolites in patients with renal failure

Interaction between vigabatrin and phenytoin.

Antiepileptic Drugs

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