Sparteine oxidation by the human liver: Absence of inhibition by mephenytoin

Jurima, M; Inaba, T.; Kalow, W.

doi:10.1038/clpt.1984.54

Cited by 17 publications

(3 citation statements)

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“…Thus, there are population differences in the gene frequency for slow debrisoquine 4-hydroxylation Woolhouse et al, 1979;Kalow et al, 1980;Mbanefo et al, 1980). This drug hydroxylation is catalyzed by the same genetically variable cytochrome P-450 which catalyzes sparteine oxidation (Boobis et al, 1983;Inaba et al, 1984b) but is different from the cytochrome P-450 responsible for the polymorphism in mephenytoin metabolism (Kupfer et al, 1982;Inaba et al, 1984a;Jurima et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

Genetic polymorphism of mephenytoin p(4′)‐hydroxylation: difference between Orientals and Caucasians.

Jurima¹,

Inaba²,

Kadar³

et al. 1985

Brit J Clinical Pharma

106

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The genetically controlled mephenytoin p(4′)‐hydroxylation capacity was determined in 118 Caucasians and 70 Orientals. After an oral dose of 50 or 100 mg of racemic mephenytoin, the amount of p(4′)‐ hydroxymephenytoin in 24 h urine was measured by gas chromatography. Bimodal distribution was found with 9/70 (13%) Orientals and 5/118 (4%) Caucasians demonstrating deficient p(4′)‐hydroxylation. The statistically significant difference between Orientals and Caucasians (P less than 0.05) was accounted for by the high incidence of poor metabolizers among the Japanese subjects, 7/31 (23%). The frequency among Chinese subjects, 2/39 (5%), was similar to the frequency among Caucasians.

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Section: Introductionmentioning

confidence: 99%

Genetic polymorphism of mephenytoin p(4′)‐hydroxylation: difference between Orientals and Caucasians.

Jurima¹,

Inaba²,

Kadar³

et al. 1985

Brit J Clinical Pharma

106

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“…An explanatory hypothesis is the possible biotransformation of QAs in the cow. So far, metabolism of individual QAs has been investigated only in rats, pigs, rabbits, and humans. ,, Studies in rats showed that sparteine was oxidized to lupanine, which was found in the urine of orally dosed rats in vivo (suspected microsomal metabolization), while lupanine was found to be presumably transformed to a hydroxyl derivative through a yet unknown pathway. , Until now, there exists no information regarding the possible metabolization of lupanine into 13α-hydroxylupanine in cows. However, conversion could explain its higher values in the morning milk.…”

Section: Resultsmentioning

confidence: 99%

Investigations on the Transfer of Quinolizidine Alkaloids from Lupinus angustifolius into the Milk of Dairy Cows

Engel

Klevenhusen

Moenning

et al. 2022

J. Agric. Food Chem.

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Lupin varieties with a low content of quinolizidine alkaloids (QAs) like blue sweet lupin (BSL) have long been used as a protein source for dairy cows. A health concern for humans may arise from the transfer of acute toxic QAs from feed into cow’s milk. This study is the first to quantify the transfer of QAs from BSL into cow’s milk with experimental and modeling methods. Four lactating dairy cows were subjected to two 7 day feeding periods with 1 and 2 kg/d BSL, respectively, each followed by a depuration period. BSL contained 1774 mg/kg dry matter total QAs. Individual milk samples were taken twice daily and QA contents in feed and milk determined with liquid chromatography–tandem mass spectrometry. Transfer of QAs into the milk was already seen with the administration of 1 kg/d BSL, with differences in transfer rates (TRs) between individual QAs. A toxicokinetic model was derived to quantify and predict QA feed-to-food transfer. For the four most prominent QAs, our model shows an α-half-life of around 0.27 d. TRs were obtained for six QAs and were between 0.13 (sparteine) and 3.74% (multiflorine). A toxicological assessment of milk containing QAs as measured in this study indicated a potential health concern.

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“…At least two similar forms of human cytochrome P-450 seem to be involved in S-mephenytoin 4-hydroxylation and the molecular basis of the polymorphism has been partly elucidated (Guengerich et al, 1988;Meier et al, 1985;Shimada et al, 1986). Polymorphisms in the oxidation of sparteine/debrisoquine and mepheytoin have been found to be independent entities Jurima et al, 1984). In contrast to the relatively large number of drugs the oxidation of which cosegregates with sparteine/debrisoquine only that of 5-phenyl-5-ethylhydantoin (Nirvanol) and mephobarbitone are known to cosegregate with mephenytoin oxidation in vivo (Jacqz et al, 1986;Kupfer & Branch, 1985;Kupfer et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

Relationship between mephenytoin oxidation polymorphism and phenytoin, methylphenytoin and phenobarbitone hydroxylation assessed in a phenotyped panel of healthy subjects.

Schellens

Wart

Breimer

1990

Brit J Clinical Pharma

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1 In a phenotyped panel of healthy subjects correlations were studied between the oxidation of mephenytoin, phenytoin, methylphenytoin and phenobarbitone, with respect to the formation of their 4-hydroxy metabolites (OH-). 2 On different occasions phenotyped extensive metabolizers (EM; n = 16) and poor metabolizers (PM; n = 4) of mephenytoin received phenytoin (100 mg), methylphenytoin (100 mg) and phenobarbitone (50 mg) and urine was collected up to 24 h. The excreted 4-hydroxy metabolites of all compounds were measured by h.p.l.c. 3 Urinary recovery of OH-phenytoin was 31.0 ± 11.7%, of OH-methylphenytoin 3.4 + 2.7% and of OH-phenobarbitone 1.4 ± 1.2%. No correlation was found between the recovery of OH-mephenytoin and OH-phenytoin. A subject who produced virtually no OH-phenytoin was an EM of mephenytoin, confirming a dissociation of mephenytoin polymorphism and phenytoin hydroxylation. 4 The correlation coefficient for OH-mephenytoin and OH-methylphenytoin recovery was 0.71 (Spearman rank, P = 0.002). The PMs of mephenytoin excreted the least amount of OH-methylphenytoin, suggesting a cosegregation of the 4-hydroxylation pathways. No correlation was found between the urinary recovery of OH-phenobarbitone and that of the other 4-hydroxy metabolites.Keywords mephenytoin polymorphism phenytoin methylphenytoin and phenobarbitone hydroxylation cytochrome P-450

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Sparteine oxidation by the human liver: Absence of inhibition by mephenytoin

Cited by 17 publications

References 0 publications

Genetic polymorphism of mephenytoin p(4′)‐hydroxylation: difference between Orientals and Caucasians.

Genetic polymorphism of mephenytoin p(4′)‐hydroxylation: difference between Orientals and Caucasians.

Investigations on the Transfer of Quinolizidine Alkaloids from Lupinus angustifolius into the Milk of Dairy Cows

Relationship between mephenytoin oxidation polymorphism and phenytoin, methylphenytoin and phenobarbitone hydroxylation assessed in a phenotyped panel of healthy subjects.

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