Influence of DH/DL alleles regulating debrisoquine oxidation on phenytoin hydroxylation

Sloan, T.P.; Idle, J R; Smith, Richard L.

doi:10.1038/clpt.1981.68

Cited by 37 publications

(10 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These unpleasant side-effects of the drug disappeared within the next 4 h. In this subject, plasma bufuralol concentrations were unusually high and carbinol concentrations low. This observation and a similar case previously reported (Balant et al, 1976) suggest a pharmacogenetic anomaly for aliphatic hydroxylation of bufuralol (Balant et al, 1978b), as recently described for alicyclic hydroxylation of debrisoquine (Mahgoub et al, 1977;Price Evans et al, 1980), N-oxidation of sparteine (Eichelbaum et al, 1979);Bertilsson et al, 1980), hydroxylation of phenytoin (Sloan et al, 1981), or other oxidated drugs (Sloan et al, 1978).…”

Section: Defective Hydroxylation Of Bufuralol Associated With Side-efsupporting

confidence: 61%

Defective hydroxylation of bufuralol associated with side‐effects of the drug in poor metabolisers [letter]

Dayer¹,

Kubli²,

Küpfer³

et al. 1982

Brit J Clinical Pharma

View full text Add to dashboard Cite

Section: Defective Hydroxylation Of Bufuralol Associated With Side-efsupporting

confidence: 61%

Defective hydroxylation of bufuralol associated with side‐effects of the drug in poor metabolisers [letter]

Dayer¹,

Kubli²,

Küpfer³

et al. 1982

Brit J Clinical Pharma

View full text Add to dashboard Cite

“…PM subjects have been shown to have relatively impaired abilities to metabolize phenacetin and guanoxan (Sloan et al, 1978), phenytoin (Sloan et al, 1981), sparteine (Bertilsson et al, 1980) and phenformin (Oates et al, 1982). We would advocate the use of the oxidation phenotyping procedure in the safety evaluation of both new and existing drugs where metabolic oxidation is a major determinant of the duration and intensity of a compounds pharmacological effects.…”

Section: Resultsmentioning

confidence: 99%

Genetically determined oxidation capacity and the disposition of debrisoquine.

Sloan¹,

Lancaster²,

Shah³

et al. 1983

Brit J Clinical Pharma

View full text Add to dashboard Cite

1 The disposition in urine of debrisoquine and its hydroxylated metabolites has been studied in subjects of the 'extensive metabolizer' (EM; n = 5) and 'poor metabolizer' (PM; n = 5) phenotypes. The 4-hydroxylation of debrisoquine by PM subjects following a 10 mg oral dose was capacity-limited and displayed significant dose-dependency over a range of 1-20 mg. In contrast, the EM subjects' ability to perform this metabolic oxidation did not deviate from first-order kinetics over a dose range of 10-40 mg. 2 The disposition of debrisoquine in plasma following a 10 mg oral dose has been studied in EM (n = 4) and PM (n = 3) subjects. Whilst PM subjects displayed significantly higher plasma levels of debrisoquine at all time points following 1 h post-dosing, and higher values for areas under the plasma concentration-time curve (EM: 105.6 + 7.0 ng ml-' h; PM: 371.4 + 22.4 ng ml-' h, 2P < 0.0001), neither debrisoquine plasma half-life (EM: 3.0 + 0.5 h; PM: 3.3 + 0.4 h) nor renal clearance of the drug (EM: 152.8 + 30.3 ml min-'; PM: 137 + 4.5 ml min-') displayed significant inter-phenotype differences. 3 The results of these investigations show that the phenotyping of individuals for debrisoquine oxidation status by means of a 'metabolic ratio' derived from a single 0-8 h urine sample has a sound kinetic basis. The kinetic differences between the two phenotypes would strongly suggest that the metabolic defect manifested in PM subjects is one of pre-systemic elimination capacity.

show abstract

“…Furthermore, it has been demonstrated that the same polymorphism controls the oxidation not only of these 2 drugs but also of other drugs, e.g. phenacetin (Idle & Smith, 1979;Ritchie et al, 1980), phenytoin (Sloan et al, 1981), phenformin (Oates et al, 1981;Wiholm et al, 1981) and nortriptyline (Mellstrom et al, 1981) (for review see Eichelbaum, 1982). Antipyrine has been used as a probe drug in studies of oxidative metabolism (Stevenson, 1977;Vesell, 1979).…”

Section: Introductionmentioning

confidence: 99%

Antipyrine metabolism in relation to polymorphic oxidations of sparteine and debrisoquine.

Eichelbaum¹,

Säwe²

1983

Brit J Clinical Pharma

View full text Add to dashboard Cite

1 Thirty-five healthy subjects who had been classified as extensive or poor metabolisers of both sparteine and debrisoquine were given a single oral dose of antipyrine. Saliva concentration of antipyrine and urinary excretion of its three major oxidation metabolites were measured. 2 All the parameters of antipyrine metabolism which were estimated had similar distributions in both the 28 EM and 7 PM genetic phenotypes defined by the metabolism of sparteine and debrisoquine.3 The clearance of antipyrine by the formation of 4-hydroxy-antipyrine and 3-hydroxy-antipyrine respectively were closely correlated (r = 0.83, P < 0.001) and both were significantly higher in smokers than in non-smokers. Demethylation of antipyrine also seemed to be influenced by smoking, but not to a statistically significant extent. These findings confirm the influence of the environmental factor of smoking in antipyrine oxidative biotransformations.

show abstract

Influence of DH/DL alleles regulating debrisoquine oxidation on phenytoin hydroxylation

Cited by 37 publications

References 1 publication

Defective hydroxylation of bufuralol associated with side‐effects of the drug in poor metabolisers [letter]

Defective hydroxylation of bufuralol associated with side‐effects of the drug in poor metabolisers [letter]

Genetically determined oxidation capacity and the disposition of debrisoquine.

Antipyrine metabolism in relation to polymorphic oxidations of sparteine and debrisoquine.

Contact Info

Product

Resources

About