Impairment of Phenytoin Parahydroxylation as a Cause of Severe Intoxication

Fa, de Wolff; Vermeij, P.; Ferrari, Paolo; Oj, Buruma; Dd, Breimer

doi:10.1097/00007691-198306000-00011

Cited by 22 publications

(4 citation statements)

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“…Thus, following the application of the panel approach to the oxidation of phenytoin and carboxymethyl-L-cysteine, it was concluded that both reactions were regulated by the same gene as that controlling the oxidation of debrisoquine (Sloan et al, 1981;Waring et al, 1983). Subsequent studies have shown that this was incorrect in both cases (de Wolff et al, 1983;Haley et al, 1985). The originators of the panel approach now suggest caution in the interpretation of results when small numbers of subjects are used (Haley etal., 1985).…”

Section: Introductionmentioning

confidence: 99%

Quinidine and the identification of drugs whose elimination is impaired in subjects classified as poor metabolizers of debrisoquine.

Speirs¹,

Murray²,

Boobis³

et al. 1986

Brit J Clinical Pharma

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Quinidine and its diastereoisomer quinine were tested in vitro for their effect on the 4-hydroxylation of debrisoquine, the O-deethylation of phenacetin and the l'-hydroxylation of bufuralol, by human liver microsomal samples; quinidine was studied for its effect on debrisoquine 4-hydroxylation in vivo. Quinidine was a potent inhibitor of the 4-hydroxylation of debrisoquine and the l'-hydroxylation of bufuralol, with IC50 values of 0.7 and 0.2 /M, being around 100 times more potent in this respect than quinine. Very much higher (1000-fold) levels of quinidine were required to inhibit the O-deethylation of phenacetin, being rather less potent in this than-quinine. Eight subjects were phenotyped for their debrisoquine oxidation status and found to be extensive metabolisers (EM). They were tested again after the co-administration of 50 mg of quinidine with the debrisoquine. The concomitant administration of quinidine increased the metabolic ratios (MRs) by a mean of 26-fold. The effects of quinidine at a dose of only 50 mg, on the metabolism of a new drug in EM subjects may prove a useful method of assessing the contribution of the debrisoquine 4-hydroxylase isozyme to the elimination of the drug tested.

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Section: Introductionmentioning

confidence: 99%

Quinidine and the identification of drugs whose elimination is impaired in subjects classified as poor metabolizers of debrisoquine.

Speirs¹,

Murray²,

Boobis³

et al. 1986

Brit J Clinical Pharma

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“…In subjects with a genetic CYP2C19 deficiency, the PHT K, was generally unchanged, whereas the V, , , for PHT metabolism was significantly (19,20). The fact that PHT plasma concentrations increase 25-35% with FBM coadministration lends support to the CYP2C 19 alternate metabolic pathway hypothesis, particularly because HPPH concentrations were for the most part decreased or unchanged despite increasing plasma PHT concentrations.…”

Section: Discussionmentioning

confidence: 86%

Coadministration of Phenytoin and Felbamate: Evidence of Additional Phenytoin Dose‐Reduction Requirements Based on Pharmacokinetics and Tolerability with Increasing Doses of Felbamate

et al. 1999

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Summary: Purpose: This open-label study investigated the pharmacokinetic interaction of phenytoin (PHT) and felbamate (FBM).Methods: Ten subjects with epilepsy receiving PHT monotherapy were administered increasing doses of FBM ( I ,200, 1,800, 2,400-3,600 mg/day) at 2-week intervals. PHT doses were reduced by 20% on an individual basis when evidence of clinically significant intolerance was present. With intolerance, the PHT dose was reduced before the next incremental FBM dose. Blood samples were analyzed for FBM, PHT, and PHT metabolite 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH).Results: Total PHT plasma concentrations increased with coadministered FBM. PHT C, , , increased from 15.9 pg/ml at baseline to 20.9 yg/ml after 1,200 mg/day FBM and to 26.8 pg/ml after 1,800 mg/day FBM. Four subjects required a 20% PHT dose reduction after 1,800 mg/day FBM and six after the administration of 2,400 mg/day FBM. All subjects required further 20% PHT reductions before 3,600 mg/day FBM. FBM C,,,, and AUC, were reduced, and apparent clearance increased compared with data from FBM monotherapy.Conclusions: With the initiation of FBM therapy in subjects receiving PHT, the PHT dosage should be reduced by 20%. Further PHT dose reductions are likely to be necessary if the FBM dose is increased. The requirements for reductions in dose might be predicted by clinical signs of PHT intolerance.

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“…Attempts to define pharmacogenetic differences using one or two standardized drugs as probes produce information that is relatively specific to the compound that is being tested. The kinetic phenotype for one drug cannot be generalized to others because of the complexity of the cytochrome P-450 system (de Wolff et al, 1983;Bach et al, 1981;Vesell, 1984;Adesnik and Atchison, 1986). Furthermore, inducing agents may affect drug-eliminating processes differently as in the case of the different effects of phenobarbital (PB) and carbamazepine (CBZ) on phenytoin (PHT) elimination (Dodson, 1982).…”

Section: Developmental Changes In Pharmacokineticsmentioning

confidence: 99%

Special Pharmacokinetic Considerations in Children

Dodson

1987

Epilepsia

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Pediatric patients have greater degrees of pharmacokinetic variability and unpredictability than adults. This variability results from the effects of pharmacogenetics, age and growth, prior and current comedication, and disease. Newborns with seizures have the least predictable dosage requirements, and their needs change as drug-eliminating mechanisms mature in the neonatal period. Infants have the highest relative capacities to eliminate antiepileptics of any age group and require the largest relative doses. In addition to age-related trends, children demonstrate the same drug-specific, pharmacokinetic phenomena that adults do, including nonlinear phenytoin elimination, nonlinear valproate binding, and autoinduction of carbamazepine. Intercurrent illness and drug interactions further modify the age-related pharmacokinetic patterns in children and make dosage requirements even more unpredictable. Recent studies have shown that febrile illness can affect drug elimination, sometimes decreasing drug levels by 50% or more. Intermittent treatment with benzodiazepines administered either orally or rectally can be an important adjunct and help minimize this type of problem for children with marginally controlled epilepsy. Intermittent benzodiazepines are also helpful for children who have febrile seizures and who need only occasional antiepileptic protection.

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Impairment of Phenytoin Parahydroxylation as a Cause of Severe Intoxication

Cited by 22 publications

References 0 publications

Quinidine and the identification of drugs whose elimination is impaired in subjects classified as poor metabolizers of debrisoquine.

Quinidine and the identification of drugs whose elimination is impaired in subjects classified as poor metabolizers of debrisoquine.

Coadministration of Phenytoin and Felbamate: Evidence of Additional Phenytoin Dose‐Reduction Requirements Based on Pharmacokinetics and Tolerability with Increasing Doses of Felbamate

Special Pharmacokinetic Considerations in Children

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