Determination of 5-(3,4-Dihydroxy-1,5-cyclohexadien-1-yl)-5-phenylhydantoin (Dihydrodiol) and Quantitative Studies of Phenytoin Metabolism in Man

Maguire, James H.; Kraus, Betsy L.; Butler, Thomas; Dudley, Kenneth H.

doi:10.1097/00007691-197901030-00009

Cited by 14 publications

(12 citation statements)

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“…Urine samples were assayed for total DHD and p-HPPH content by the method of Maguire et al (1979). Subsequently, urine samples were incubated with P-glucuronidase and DHD and p-HPPH fractions were collected according to the method described for assay of DHD diastereomeric content by reverse-phase h.p.l.c.…”

Section: Methodsmentioning

confidence: 99%

“…Plasma samples were assayed for phenytoin concentration by the Epilepsy and Anticonvulsant Drug Research Laboratory of the University of North Carolina with the use of an on-column methylation gas chromatographic assay (Dudley et al, 1977). Urine samples were assayed for total DHD and p-HPPH content by the method of Maguire et al (1979). Subsequently, urine samples were incubated with P-glucuronidase and DHD and p-HPPH fractions were collected according to the method described for assay of DHD diastereomeric content by reverse-phase h.p.l.c.…”

Section: Methodsmentioning

confidence: 99%

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Apparently normal phenytoin metabolism in a patient with phenytoin‐ induced rash and lymphadenopathy.

Maguire

Wettrell

Rane

1987

Brit J Clinical Pharma

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A 10‐year old female on phenytoin therapy developed a rash and lymphadenopathy. H.p.l.c. assays of urinary metabolites indicated no differences in stereoselective metabolism of phenytoin to phenolic and dihydrodiol metabolites as compared with volunteers given the drug or with pediatric patients without adverse reactions. This suggests that no obvious difference in stereoselective metabolism of phenytoin to potentially toxic arene oxides exists between this patient and other patients on phenytoin. Our results are consistent with the hypothesis that differences in peripheral detoxication of phenytoin arene oxides and not differences in hepatic metabolism of phenytoin may be responsible for such adverse reactions.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Apparently normal phenytoin metabolism in a patient with phenytoin‐ induced rash and lymphadenopathy.

Maguire

Wettrell

Rane

1987

Brit J Clinical Pharma

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“…The predominant urinary metabolite is 5-(4-hydroxyphenyl)-5-phenylhydantoin (pHPPH) (70), which is present in human urine as 50-75% of an ingested dose (68) and is primarily excreted as a glucuronide conjugate (69). A dihydrodiol metabolite, 5-( 3,4-dihydroxy-1,5-~yclohexadien-1 -yl)-5-phenylhydantoin (PHT-DHD) was identified in rat urine (71) and may constitute 3-13% of the human urinary excretion of an ingested dose (72). Production of PHT-DHD is taken as evidence of formation of an epoxide intermediate (73).…”

Section: Metabolismmentioning

confidence: 99%

The Embryotoxicity of Phenytoin: An Update on Possible Mechanisms

Hansen

1991

Experimental Biology and Medicine

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PHT has multiple effects in adult humans and animals, and there is no reason to assume that it will not have multiple effects in embryos and fetuses. Although one of the first associations between anticonvulsant therapy and an adverse development effect in humans was noted in 1964 (104), the mechanism(s) whereby these adverse effects occur has thus far eluded research efforts. In this review, I have focused on three possible mechanisms. Overall, the evidence does not appear to implicate folate deficiency in PHT-induced embryotoxicity. A role for glucocorticoids or interaction between PHT and the glucocorticoid receptor has not been ruled out. However, a significant amount of work remains to be done to examine the involvement of the arachidonic acid cascade in PHT-induced embryotoxicity in vivo. The bulk of the experimental evidence would seem to favor a role for the generation of a reactive intermediate and its subsequent binding to embryonic macromolecules. This metabolite(s) has not been identified. Additionally, the association between covalent binding of metabolites and embryotoxicity remains simply an association; a causal relationship has not been established. Much work remains to be done to determine whether any of these possibilities, some other possibility, or a combination of several mechanisms will explain the adverse development effects of this very important, therapeutically useful anticonvulsant.

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“…Samples of racemic p-HPPH and 5-(3-hydroxyphenyl)-5-phenylhydantoin (m-HPPH) were available from a previous study (Maguire et al, 1979). The PHT metabolites and the internal standard ( Fig.…”

Section: Chemicalsmentioning

confidence: 99%

“…All urine samples were assayed by the procedure of Maguire et al (1979), which uses an acid hydrolysis method to allow quantitation of p-HPPH and m-HPPH (from dehydration of DHD) with subsequent calculation of both DHD and p-HPPH content.…”

Section: Urinary Dhd and P-hpph Assaysmentioning

confidence: 99%

Quantitative Estimation of Catechol/Methylcatechol Pathways in Human Phenytoin Metabolism

Maguire

1988

Epilepsia

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A gas-liquid chromatographic (GLC) assay utilizing an on-column methylation technique has been developed to assay urinary concentration of a phenytoin (5,5-diphenylhydantoin, PHT) metabolite, 5-(4-hydroxy-3-methoxyphenyl)-5-phenylhydantoin (MCAT). Assay of MCAT in 35 24-h urine samples from patients receiving chronic phenytoin (PHT) therapy indicated that 0.3-4.0% of the daily dose could be accounted for as MCAT. The GLC assay was specific for MCAT, and provided a minimal estimate of the fraction of the PHT dose being metabolized via the catechol/MCAT route. Multiple regression analyses indicated that the amount of urinary MCAT was dependent on the quantities of both dihydrodiol (DHD) and p-phenolic (p-HPPH) metabolites. Oxidative pathways involving both DHD and p-HPPH as substrates appear to be responsible for catechol/MCAT production.

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Determination of 5-(3,4-Dihydroxy-1,5-cyclohexadien-1-yl)-5-phenylhydantoin (Dihydrodiol) and Quantitative Studies of Phenytoin Metabolism in Man

Cited by 14 publications

References 0 publications

Apparently normal phenytoin metabolism in a patient with phenytoin‐ induced rash and lymphadenopathy.

Apparently normal phenytoin metabolism in a patient with phenytoin‐ induced rash and lymphadenopathy.

The Embryotoxicity of Phenytoin: An Update on Possible Mechanisms

Quantitative Estimation of Catechol/Methylcatechol Pathways in Human Phenytoin Metabolism

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