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Leif Bertilsson - One of the best experts on this subject based on the ideXlab platform.

  • no sex related differences but significant inhibition by oral contraceptives of cyp2c19 activity as measured by the probe drugs Mephenytoin and omeprazole in healthy swedish white subjects
    Clinical Pharmacology & Therapeutics, 2000
    Co-Authors: Leif Bertilsson, Gunnel Tybring, Kari Laine
    Abstract:

    Background Although it is known that the use of oral contraceptives inhibits oxidative drug metabolism, there is little information regarding their effect on CYP2C19 activity. Moreover, earlier reports suggest that there may be differences in CYP2C19 activity between men and women. Objective We sought to assess the effect of sex and intake of oral contraceptives on CYP2C19 activity as measured by the probe drugs Mephenytoin and omeprazole. Methods To determine CYP2C19 activity in white Swedish subjects, 644 subjects previously phenotyped with Mephenytoin and 175 subjects phenotyped with omeprazole were investigated. The 8-hour urinary Mephenytoin S/R ratio after ingestion of 100 mg Mephenytoin and the plasma concentration ratio of omeprazole/hydroxyomeprazole at 3 hours after ingestion of 20 mg omeprazole were used as measures of CYP2C19 activity. Differences in these ratios and in their frequency distributions were then examined among women with and without oral contraceptives and men. In addition, nearly all subjects in the omeprazole group had been genotyped with regard to the CYP2C19*2 (m1) allele. Subjects homozygous for the CYP2C19*2 allele were excluded from the study. Results The median Mephenytoin S/R ratio was 2.5-fold higher in the subgroup of women taking oral contraceptives compared with either women not taking oral contraceptives (P < .001) or men (P < .001). Similarly, the mean omeprazole/hydroxyomeprazole ratio was twice as high in the oral contraceptive group compared with women not taking oral contraceptives (P < .001) or men (P < .001). However, no differences were evident between women not taking oral contraceptives and men in either the Mephenytoin group (P = .48) or the omeprazole group (P = .77). The oral contraceptive–induced inhibitory effect on CYP2C19 activity was similar between the CYP2C19*1/*1 and *1/*2 genotypes, and they were independent of age. Conclusions Intake of oral contraceptives significantly inhibits CYP2C19 activity, but there is no true sex-related difference in CYP2C19 activity in healthy, white, Swedish subjects. Clinical Pharmacology & Therapeutics (2000) 68, 151–159; doi: 10.1067/mcp.2000.108949

  • An S-Mephenytoin cysteine conjugate identified in urine of extensive but not of poor metabolizers of S-Mephenytoin.
    Pharmacogenetics, 1997
    Co-Authors: Gunnel Tybring, Jan Nordin, Toms Bergman, Leif Bertilsson
    Abstract:

    : A conjugate of S-Mephenytoin excreted in urine of extensive but not of poor metabolizers of S-Mephenytoin has previously been reported. This conjugate, which is easily hydrolysed back to S-Mephenytoin, has now been isolated and identified in urine from one extensive metabolizer after a single dose of 100 mg racemic Mephenytoin. High performance liquid chromatography purification, followed by gas chromatographic, mass spectrometric and amino acid analyses showed that the isolated compound is a cysteine conjugate of S-Mephenytoin. The significant mass spectrometric ions have been confirmed in three additional extensive metabolizers of S-Mephenytoin, but were not detectable in urine from three poor metabolizer subjects. The exact structure of the conjugate is unknown, but we suggest that an S-N bond between cysteine and S-Mephenytoin is formed via an oxidative radical mechanism catalyzed by CYP2C19.

  • s Mephenytoin hydroxylation phenotype and cyp2c19 genotype among ethiopians
    Pharmacogenetics, 1996
    Co-Authors: Irene Persson, Leif Bertilsson, Eleni Aklillu, Fredrick Rodrigues, Magnus Ingelmansundberg
    Abstract:

    : The polymorphic metabolism of S-Mephenytoin and the distribution of two known deleterious mutant CYP2C19 alleles was determined among 114 healthy unrelated black Ethiopians. Six subjects (5.2%) were poor metabolizers (PMs) of S-Mephenytoin. The frequencies of the defective CYP2C19*2 (CYP2C19m1) and CYP2C19*3 (CYP2C19m2) alleles were 0.14 and 0.02, respectively. Three of the PMs were homozygous for the CYP2C19*2 allele and the remaining three PMs were heterozygous for both the CYP2C19*2 and CYP2C19*3 mutant alleles. It is concluded that the frequency of PMs for S-Mephenytoin is similar in Ethiopians, Zimbabweans and Caucasians and that the CYP2C19*3 allele, for the first time identified in a black population, together with the CYP2C19*2 allele account for all of the defective CYP2C19 alleles among the Ethiopian PMs.

  • Frequency of S-Mephenytoin hydroxylation deficiency in 373 Spanish subjects compared to other Caucasian populations.
    European Journal of Clinical Pharmacology, 1993
    Co-Authors: J. Reviriego, Adrián Llerena, Maria J. Valdivielso, Leif Bertilsson, Juan Antonio Carrillo, Julio Benítez
    Abstract:

    We have investigated the prevalence of poor metabolisers (PM) of S-Mephenytoin in 373 unrelated, healthy Spanish Caucasian subjects, based on the enantiomeric S/R Mephenytoin ratio in urine collected 0–8 h and 24–32 h after intake of the racemic drug.

  • Reproducibility over time of Mephenytoin and debrisoquine hydroxylation phenotypes.
    Pharmacology & Toxicology, 1993
    Co-Authors: Adrián Llerena, Maria J. Valdivielso, Julio Benítez, Leif Bertilsson
    Abstract:

    : Mephenytoin and debrisoquine hydroxylation phenotypes were determined twice in 15 Spanish healthy volunteers with an interval of about one year. The phenotype assignment did not change in any subject for either debrisoquine or Mephenytoin. Among extensive metabolisers of Mephenytoin, there was a slight increase (P = 0.04) of the Mephenytoin-S/R enantiomeric ratio over the study period. The family members of a poor metaboliser of Mephenytoin were phenotyped, and the heterozygous extensive metabolisers were found to have higher Mephenytoin-S/R ratios than other extensive metabolisers suggesting a correlation between the genotype and the S/R ratio.

Hong-hao Zhou - One of the best experts on this subject based on the ideXlab platform.

  • the induction effect of rifampicin on activity of Mephenytoin 4 hydroxylase related to m1 mutation of cyp2c19 and gene dose
    British Journal of Clinical Pharmacology, 1998
    Co-Authors: Huajun Feng, Song-lin Huang, Wei Wang, Hong-hao Zhou
    Abstract:

    Aims To determine the induction effect of rifampicin on the activity of 4′-hydroxylase in poor metabolizers (PMs) with m1 mutation of S-Mephenytoin 4′-hydroxylation and the relationship of the effect with gene dose. Methods Seven extensive metabolizers (EMs) of S-Mephenytoin 4′-hydroxylation and five PMs with m1 mutation were chosen to take rifampicin 300 mg day−1 orally for 22 days. Prior to and after rifampicin treatment, each subject was given racemic Mephenytoin 100 mg. The 4′-hydroxyMephenytoin (4′-OH-MP) excreted in the 0–24 h urine and Mephenytoin S/R ratio in the 0–8 h urine were determined by h.p.l.c. and GC, respectively. Results In all EMs, the excretion of 4′-OH-MP in the 0–24 h urine was increased by 146.4±17.9%, 0–8 h urinary Mephenytoin S/R ratio was decreased by 77.3±8.8%, the percentage increase in the 0–24 h excretion of 4′-OH-MP in those CYP2C19 homozygous (wt/wt) was greater than that in those heterozygous (wt/m1 and wt/m2 ) (203.9±42.5%vs 69.6±4.1%). 0–8 h urinary Mephenytoin S/R ratio of those PMs with m1 mutation was decreased by 9.6%, the amount of 4′-OH-MP excreted in the 0–24 h urine was increased by 80.1±48.0%. Conclusions The activity of 4′-hydroxylase of PMs with m1 mutation of S-Mephenytoin 4′-hydroxylation can be induced by rifampicin and the inducing effect of rifampicin on 4′-hydroxylase is gene dependent.

  • No correlation between side-chain of propranolol oxidation and S-Mephenytoin 4'-hydroxylase activity.
    Acta Pharmacologica Sinica, 1997
    Co-Authors: Zhen-hua Xu, Song-lin Huang, Jin-xiang Wu, Chang-hong Jiang, Hong-hao Zhou
    Abstract:

    AIM: To determine if any correlation between the side-chain oxidative capacity for propranolol and S-Mephenytoin 4'-hydroxylase (cytochrome P-450 2C19, CYP2C19) activity in healthy Chinese of Han nationality. METHODS: S-Mephenytoin oxidative metabolite 4'-hydroxyMephenytoin (4'OH-M), S- and R-Mephenytoin, and naphthoxyl-actic acid (NLA) excreted in urine, and propranolol in plasma were measured after 14 healthy extensive metabolizers of S-Mephenytoin oxidation were given a single oral dose of racemic Mephenytoin 100 mg and racemic propranolol 80 mg, respectively. S/R-Mephenytoin in urine was determined by chiral capillary gas chromatography with nitrogen-phosphorus detection, 4'-OH-M in urine by reversed-phase liquid chromatography (RPLC) with ultraviolet detection, and plasma propranolol or urinary NLA by the RPLC with fluorescence detection. RESULTS: No significant correlations were found between the partial metabolic clearance (Clm) of propranolol to NLA and 8 h urinary S/R ratio of Mephenytoin (rs = -0.0484; P = 0.8695), nor between the Clm and log10 of 8 h urinary excretion of 4'-OH-M (rs = -0.1077; P = 0.7140). CONCLUSIONS: CYP2C19 is not a principal P-450 isozyme responsible for the in vivo side-chain oxidation of propranolol in the Chinese.

  • the elimination of diazepam in chinese subjects is dependent on the Mephenytoin oxidation phenotype
    British Journal of Clinical Pharmacology, 1996
    Co-Authors: Nan He, Yiqing Lu, Hong-hao Zhou
    Abstract:

    : 1. The disposition of diazepam and desmethyldiazepam was studied in 21 healthy male Chinese subjects who were phenotyped with Mephenytoin. Four poor metabolizers (PM) were identified by phenotyping with Mephenytoin and by genotyping for CYP2C19. 2. Serum diazepam and desmethyldiazepam concentrations were measured by high performance liquid chromatography in samples drawn up to 24 days after administration. 3. The plasma elimination half-lives of diazepam (100.8 +/- 32.3 h) and desmethyldiazepam (219.9 +/- 62.7 h) in PMs were significantly longer than those (34.7 +/- 23.0 h for diazepam, 103.1 +/- 25.9 h for desmethyldiazepam) of the 17 phenotyped extensive metabolizers (EM), and those (30.8 +/- 24.9 h for diazepam, 103.1 +/- 27.5 h for desmethyldiazepam) of the five genotyped EMs. 4. The Mephenytoin S/R ratios were significantly correlated with the plasma half-lives of diazepam (r = 0.543, P < 0.05) and desmethyldiazepam (r = 0.522, P < 0.05), and with the clearance (r = -0.524, P < 0.05) of diazepam in 21 subjects. 5. These results are compatible with the conclusion that both diazepam and desmethyldiazepam are metabolized by cytochrome P450 CYP2C19 in the Chinese population. 6. The Mephenytoin S/R ratios in nine EMs who drank alcohol frequently were significantly higher than those of seven EMs who were non-drinkers, but the plasma kinetics of diazepam and desmethyldiazepam were not significantly different between the two groups. The explanation for these finding is not clear.

  • genetic polymorphisms of debrisoquine and s Mephenytoin oxidation metabolism in chinese populations a meta analysis
    Pharmacogenetics, 1996
    Co-Authors: Zhen-hua Xu, Song-lin Huang, Fan Dian Zeng, Hong-hao Zhou
    Abstract:

    : Chinese data on the polymorphic metabolism of debrisoquine, metoprolol, codeine and Mephenytoin were collected and re-analysed using a meta-analysis method. There were no significant differences in the incidences of poor metabolizer (PM) between the separate series of debrisoquine, metoprolol and codeine, which are the three probe drugs reflecting the same enzyme polymorphism. PMs were detected at low frequencies for debrisoquine (1.20%; 95% confidence interval, CI: 0.67-1.98%), metoprolol (0.72%; CI: 0.29-1.49%) and codeine (0.48%, CI: 0.01-2.68%). The overall estimate of PM was 0.95% (CI: 0.60-1.42%) based on the 2427 determinations of all three probe drugs. The overall mean of PM of Mephenytoin was 14.32% (12.26-16.38%) in the 1117 subjects. In summary, the present meta-analysis determined the accurate incidences of the genetic deficiency of S-Mephenytoin 4'-hydroxylase (cytochrome P450 2C19) and debrisoquine hydroxylase (cytochrome P450 2D6) in Chinese populations.

  • genetic analysis of the s Mephenytoin polymorphism in a chinese population
    Clinical Pharmacology & Therapeutics, 1995
    Co-Authors: Sonia M F De Morais, Joyce A Goldstein, Songling Huang, Yiqing Lu, Zhousheng Xiao, Hong-hao Zhou
    Abstract:

    The 4'-hydroxylation of S-Mephenytoin exhibits a polymorphism in humans, with the poor metabolizer phenotype exhibiting a lower frequency in white (3% to 5%) than in Oriental populations (13% to 23%). Two mutations in CYP2C19 (CYP2C19m1 and CYP2C19m2) have recently been described that account for ~85% of white and 100% of Japanese poor metabolizers. This study examines whether these mutations account for the poor metabolizer phenotype in the Chinese population. The metabolism of S-Mephenytoin exhibited a bimodal distribution in 244 unrelated Chinese subjects, although the distribution of the two phenotypes overlapped. In 75 selected Chinese subjects, CYP2C19 genotype analysis predicted the phenotype with 100% accuracy. The frequency of the poor metabolizer phenotype was ~11% (95% confidence interval 7% to 15%). The frequency of the CYP2C19m1 allele was 0.289, whereas that of CYP2C19m2 was 0.044. Homozygous extensive metabolizers had slightly lower ratios of SR-Mephenytoin compared with heterozygous extensive metabolizers, showing a gene-dosage effect. These data show the advantages of genotype analysis in investigations of the Mephenytoin phenotype in Oriental subjects. Clinical Pharmacology & Therapeutics (1995) 58, 404–411; doi:

Kim Brosen - One of the best experts on this subject based on the ideXlab platform.

  • a novel transversion in the intron 5 donor splice junction of cyp2c19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug s Mephenytoin
    Journal of Pharmacology and Experimental Therapeutics, 1999
    Co-Authors: Gordon C Ibeanu, Kim Brosen, P Dayer, Grant R Wilkinson, Burhan I Ghanayem, Joyce A Blaisdell, Ronald J Ferguson, Simone Benhamou, Christine Bouchardy, Joyce A Goldstein
    Abstract:

    Cytochrome P-450 (CYP) 2C19 is responsible for the metabolism of a number of therapeutic agents such as S -Mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Genetic polymorphisms in this enzyme are responsible for the poor metabolizers (PM) of Mephenytoin, which represent ∼13–23% of Asians and 3–5% of Caucasians. Several polymorphisms contribute to this phenotype. We have isolated two new allelic variants that contribute to the PM phenotype in Caucasians. CYP2C19*7 contained a single T → A nucleotide transversion in the invariant GT at the 5′ donor splice site of intron 5. The second PM allele , CYP2C19*8, consisted of a T358C nucleotide transition in exon 3 that results in a Trp120Arg substitution. In a bacterial expression system, CYP2C198 protein exhibited a dramatic (∼90% and 70%) reduction in the metabolism of S -Mephenytoin and tolbutamide, respectively, when compared with the wild-type CYP2C191B protein. Restriction fragment length polymerase chain reaction tests were developed to identify the new allelic variants.

  • Chloroguanide metabolism in relation to the efficacy in malaria prophylaxis and the S‐Mephenytoin oxidation in Tanzanians
    Clinical Pharmacology & Therapeutics, 1996
    Co-Authors: Erik Skjelbo, Theonest K. Mutabingwa, Karin Kramer Nielsen, Lars F. Gram, Ib C. Bygbjerg, Kim Brosen
    Abstract:

    S-Mephenytoin and chloroguanide (proguanil) oxidation was studied in 216 Tanzanians. The Mephenytoin S/R ratio in urine ranged from 0.9, were arbitrarily defined as poor metabolizers of Mephenytoin. The chloroguanide/cycloguanil ratio ranged from 0.82 to 249. There was a significant correlation between the Mephenytoin S/R ratio and the chloroguanide/cycloguanil ratios (rs = 0.73; p < 0.00001). This indicates that cytochrome P4502C19 or CYP2C19 is a major enzyme that catalyzes the bioactivation of chloroguanide to cycloguanil. Chloroguanide is a pro-drug, and hence a low CYP2C19 activity may lead to prophylactic failure caused by inadequate formation of cycloguanil. Fifty-eight women who previously took either 200 mg chloroguanide daily (n = 26) or 200 mg chloroguanide daily plus 300 mg chloroquine weekly (n = 32) in a malaria chemoprophylaxis study showed that there was a significant correlation between the number of earlier breakthrough parasitemia episodes and the chloroguanide/cycloguanil ratio (rs = 0.30; p = 0.02). The breakthrough rate did not correlate with the S/R Mephenytoin ratio. However, other factors, such as exposure to mosquitoes and sensitivity of the plasmodium to cycloguanil, are probably more important. Clinical Pharmacology & Therapeutics (1996) 59, 304–311; doi:

  • chloroguanide metabolism in relation to the efficacy in malaria prophylaxis and the s Mephenytoin oxidation in tanzanians
    Clinical Pharmacology & Therapeutics, 1996
    Co-Authors: Erik Skjelbo, Theonest K. Mutabingwa, Karin Kramer Nielsen, Lars F. Gram, Ib C. Bygbjerg, Kim Brosen
    Abstract:

    S-Mephenytoin and chloroguanide (proguanil) oxidation was studied in 216 Tanzanians. The Mephenytoin S/R ratio in urine ranged from 0.9, were arbitrarily defined as poor metabolizers of Mephenytoin. The chloroguanide/cycloguanil ratio ranged from 0.82 to 249. There was a significant correlation between the Mephenytoin S/R ratio and the chloroguanide/cycloguanil ratios (rs = 0.73; p < 0.00001). This indicates that cytochrome P4502C19 or CYP2C19 is a major enzyme that catalyzes the bioactivation of chloroguanide to cycloguanil. Chloroguanide is a pro-drug, and hence a low CYP2C19 activity may lead to prophylactic failure caused by inadequate formation of cycloguanil. Fifty-eight women who previously took either 200 mg chloroguanide daily (n = 26) or 200 mg chloroguanide daily plus 300 mg chloroquine weekly (n = 32) in a malaria chemoprophylaxis study showed that there was a significant correlation between the number of earlier breakthrough parasitemia episodes and the chloroguanide/cycloguanil ratio (rs = 0.30; p = 0.02). The breakthrough rate did not correlate with the S/R Mephenytoin ratio. However, other factors, such as exposure to mosquitoes and sensitivity of the plasmodium to cycloguanil, are probably more important. Clinical Pharmacology & Therapeutics (1996) 59, 304–311; doi:

  • S‐Mephenytoin, sparteine and debrisoquine oxidation: genetic polymorphisms in a Turkish population.
    British Journal of Clinical Pharmacology, 1994
    Co-Authors: Nursabah E. Basci, Kim Brosen, Atilla Bozkurt, A Isimer, A Sayal, Kayaalp So
    Abstract:

    A Mephenytoin test was carried out in 106 unrelated healthy Turkish volunteers. Racemic Mephenytoin was coadministered with either debrisoquine or sparteine. The S/R Mephenytoin ratio ranged from < 0.1 to 0.73 in 105 subjects, accordingly phenotyped as extensive metabolisers. One subject had an S/R Mephenytoin ratio of 1.02, showing that he was a poor metaboliser of Mephenytoin (0.94%, confidence interval 0.25% and 13.65%). In 48 subjects, the metabolic ratios of debrisoquine and sparteine were correlated significantly (rs = 0.61, P < 0.001).

  • single dose kinetics of clomipramine relationship to the sparteine and s Mephenytoin oxidation polymorphisms
    Clinical Pharmacology & Therapeutics, 1994
    Co-Authors: Karin Kramer Nielsen, Kim Brosen, M Jeppe G Hansen, Lars F. Gram
    Abstract:

    The influence of the sparteine and the S-Mephenytoin oxidation polymorphisms on the kinetics of clomipramine were investigated in 25 healthy volunteers: 10 extensive metabolizers of sparteine and Mephenytoin (EMs/EMm), nine poor metabolizers of sparteine and extensive metabolizers of Mephenytoin (PMs/EMm), five extensive metabolizers of sparteine and poor metabolizers of Mephenytoin (EMs/PMm), and one poor metabolizer of sparteine and Mephenytoin (PMs/PMm). A single oral dose of 100 mg clomipramine hydrochloride was given to each subject after an overnight fast. Serum and urine levels of clomipramine and its metabolites were monitored after 1, 2, 3, 4, 6, 8, 11, 14, 24, 36, 48, and 96 hours. Additional serum was monitored after 6, 9, 12, and 15 days in the poor metabolizers. 2-Hydroxyclomi-pramine was undetectable in most subjects before enzymatic hydrolysis of serum and urine. The total median clearance of clomipramine was 99 L · hr−1 (range, 68 to 210) in the EMs/EMm subjects, 56 L · hr−1 (range, 37 to 183) in the PMs /EMm subjects, 66 L · hr−1 (range, 37 to 89) in the EMs/PMm subjects, and 43 L · hr−1 in the PMs /EMm subject. It was significantly lower in PMs/EMm and EMs/PMm subjects compared with EMs/EMm subjects (p = 0.006 and 0.028, respectively; Mann-Whitney). In addition, the formation clearance of 2-hydroxyclomipramine and the hydroxylation indexes were significantly lower in PMs/EMm subjects, as was the demethylation index in EMs/PMm subjects compared with EMs/EMm subjects. Our data thus provide evidence that the 2- and 8-hydroxylation of clomipramine are catalyzed by CYP2D6 and that the N-demethylation is catalyzed in part by CYP2C. Clinical Pharmacology and Therapeutics (1994) 55, 518–527; doi:10.1038/clpt.1994.65

Lars F. Gram - One of the best experts on this subject based on the ideXlab platform.

  • Chloroguanide metabolism in relation to the efficacy in malaria prophylaxis and the S‐Mephenytoin oxidation in Tanzanians
    Clinical Pharmacology & Therapeutics, 1996
    Co-Authors: Erik Skjelbo, Theonest K. Mutabingwa, Karin Kramer Nielsen, Lars F. Gram, Ib C. Bygbjerg, Kim Brosen
    Abstract:

    S-Mephenytoin and chloroguanide (proguanil) oxidation was studied in 216 Tanzanians. The Mephenytoin S/R ratio in urine ranged from 0.9, were arbitrarily defined as poor metabolizers of Mephenytoin. The chloroguanide/cycloguanil ratio ranged from 0.82 to 249. There was a significant correlation between the Mephenytoin S/R ratio and the chloroguanide/cycloguanil ratios (rs = 0.73; p < 0.00001). This indicates that cytochrome P4502C19 or CYP2C19 is a major enzyme that catalyzes the bioactivation of chloroguanide to cycloguanil. Chloroguanide is a pro-drug, and hence a low CYP2C19 activity may lead to prophylactic failure caused by inadequate formation of cycloguanil. Fifty-eight women who previously took either 200 mg chloroguanide daily (n = 26) or 200 mg chloroguanide daily plus 300 mg chloroquine weekly (n = 32) in a malaria chemoprophylaxis study showed that there was a significant correlation between the number of earlier breakthrough parasitemia episodes and the chloroguanide/cycloguanil ratio (rs = 0.30; p = 0.02). The breakthrough rate did not correlate with the S/R Mephenytoin ratio. However, other factors, such as exposure to mosquitoes and sensitivity of the plasmodium to cycloguanil, are probably more important. Clinical Pharmacology & Therapeutics (1996) 59, 304–311; doi:

  • chloroguanide metabolism in relation to the efficacy in malaria prophylaxis and the s Mephenytoin oxidation in tanzanians
    Clinical Pharmacology & Therapeutics, 1996
    Co-Authors: Erik Skjelbo, Theonest K. Mutabingwa, Karin Kramer Nielsen, Lars F. Gram, Ib C. Bygbjerg, Kim Brosen
    Abstract:

    S-Mephenytoin and chloroguanide (proguanil) oxidation was studied in 216 Tanzanians. The Mephenytoin S/R ratio in urine ranged from 0.9, were arbitrarily defined as poor metabolizers of Mephenytoin. The chloroguanide/cycloguanil ratio ranged from 0.82 to 249. There was a significant correlation between the Mephenytoin S/R ratio and the chloroguanide/cycloguanil ratios (rs = 0.73; p < 0.00001). This indicates that cytochrome P4502C19 or CYP2C19 is a major enzyme that catalyzes the bioactivation of chloroguanide to cycloguanil. Chloroguanide is a pro-drug, and hence a low CYP2C19 activity may lead to prophylactic failure caused by inadequate formation of cycloguanil. Fifty-eight women who previously took either 200 mg chloroguanide daily (n = 26) or 200 mg chloroguanide daily plus 300 mg chloroquine weekly (n = 32) in a malaria chemoprophylaxis study showed that there was a significant correlation between the number of earlier breakthrough parasitemia episodes and the chloroguanide/cycloguanil ratio (rs = 0.30; p = 0.02). The breakthrough rate did not correlate with the S/R Mephenytoin ratio. However, other factors, such as exposure to mosquitoes and sensitivity of the plasmodium to cycloguanil, are probably more important. Clinical Pharmacology & Therapeutics (1996) 59, 304–311; doi:

  • single dose kinetics of clomipramine relationship to the sparteine and s Mephenytoin oxidation polymorphisms
    Clinical Pharmacology & Therapeutics, 1994
    Co-Authors: Karin Kramer Nielsen, Kim Brosen, M Jeppe G Hansen, Lars F. Gram
    Abstract:

    The influence of the sparteine and the S-Mephenytoin oxidation polymorphisms on the kinetics of clomipramine were investigated in 25 healthy volunteers: 10 extensive metabolizers of sparteine and Mephenytoin (EMs/EMm), nine poor metabolizers of sparteine and extensive metabolizers of Mephenytoin (PMs/EMm), five extensive metabolizers of sparteine and poor metabolizers of Mephenytoin (EMs/PMm), and one poor metabolizer of sparteine and Mephenytoin (PMs/PMm). A single oral dose of 100 mg clomipramine hydrochloride was given to each subject after an overnight fast. Serum and urine levels of clomipramine and its metabolites were monitored after 1, 2, 3, 4, 6, 8, 11, 14, 24, 36, 48, and 96 hours. Additional serum was monitored after 6, 9, 12, and 15 days in the poor metabolizers. 2-Hydroxyclomi-pramine was undetectable in most subjects before enzymatic hydrolysis of serum and urine. The total median clearance of clomipramine was 99 L · hr−1 (range, 68 to 210) in the EMs/EMm subjects, 56 L · hr−1 (range, 37 to 183) in the PMs /EMm subjects, 66 L · hr−1 (range, 37 to 89) in the EMs/PMm subjects, and 43 L · hr−1 in the PMs /EMm subject. It was significantly lower in PMs/EMm and EMs/PMm subjects compared with EMs/EMm subjects (p = 0.006 and 0.028, respectively; Mann-Whitney). In addition, the formation clearance of 2-hydroxyclomipramine and the hydroxylation indexes were significantly lower in PMs/EMm subjects, as was the demethylation index in EMs/PMm subjects compared with EMs/EMm subjects. Our data thus provide evidence that the 2- and 8-hydroxylation of clomipramine are catalyzed by CYP2D6 and that the N-demethylation is catalyzed in part by CYP2C. Clinical Pharmacology and Therapeutics (1994) 55, 518–527; doi:10.1038/clpt.1994.65

  • Single‐dose kinetics of clomipramine: Relationship to the sparteine and S‐Mephenytoin oxidation polymorphisms
    Clinical Pharmacology & Therapeutics, 1994
    Co-Authors: Karin Kramer Nielsen, Kim Brosen, M G Jeppe Hansen, Lars F. Gram
    Abstract:

    The influence of the sparteine and the S-Mephenytoin oxidation polymorphisms on the kinetics of clomipramine were investigated in 25 healthy volunteers: 10 extensive metabolizers of sparteine and Mephenytoin (EMs/EMm), nine poor metabolizers of sparteine and extensive metabolizers of Mephenytoin (PMs/EMm), five extensive metabolizers of sparteine and poor metabolizers of Mephenytoin (EMs/PMm), and one poor metabolizer of sparteine and Mephenytoin (PMs/PMm). A single oral dose of 100 mg clomipramine hydrochloride was given to each subject after an overnight fast. Serum and urine levels of clomipramine and its metabolites were monitored after 1, 2, 3, 4, 6, 8, 11, 14, 24, 36, 48, and 96 hours. Additional serum was monitored after 6, 9, 12, and 15 days in the poor metabolizers. 2-Hydroxyclomi-pramine was undetectable in most subjects before enzymatic hydrolysis of serum and urine. The total median clearance of clomipramine was 99 L · hr−1 (range, 68 to 210) in the EMs/EMm subjects, 56 L · hr−1 (range, 37 to 183) in the PMs /EMm subjects, 66 L · hr−1 (range, 37 to 89) in the EMs/PMm subjects, and 43 L · hr−1 in the PMs /EMm subject. It was significantly lower in PMs/EMm and EMs/PMm subjects compared with EMs/EMm subjects (p = 0.006 and 0.028, respectively; Mann-Whitney). In addition, the formation clearance of 2-hydroxyclomipramine and the hydroxylation indexes were significantly lower in PMs/EMm subjects, as was the demethylation index in EMs/PMm subjects compared with EMs/EMm subjects. Our data thus provide evidence that the 2- and 8-hydroxylation of clomipramine are catalyzed by CYP2D6 and that the N-demethylation is catalyzed in part by CYP2C. Clinical Pharmacology and Therapeutics (1994) 55, 518–527; doi:10.1038/clpt.1994.65

  • pharmacokinetics of citalopram in relation to the sparteine and the Mephenytoin oxidation polymorphisms
    Therapeutic Drug Monitoring, 1993
    Co-Authors: Soren H Sindrup, Kim Brosen, M G J Hansen, T Aaesjorgensen, K F Overo, Lars F. Gram
    Abstract:

    Summary The relationship between the metabolism of the selective serotonin reuptake inhibitor citalopram and the sparteine and Mephenytoin oxidation polymorphisms was studied in 24 healthy male volunteers, constituting panels of extensive metabolizers of sparteine and Mephenytoin (n = 10), poor metabolizers of sparteine (n = 8), and poor metabolizers of Mephenytoin (n = 6). Each subject was given 40 mg/day citalopram for 10 days and citalopram, and its des- and didesmethylmetabolites were assayed in serum and urine. Using a nonenantioselective analytical method (high-performance liquid chromatography), it was shown that the citalopram elimination partially depends on the Mephenytoin oxygenase, since steady-state serum concentration, half-life, and area under the serum concentration/time curve for citalopram were significantly higher in poor metabolizers of Mephenytoin than in extensive metabolizers of Mephenytoin. Both citalopram total clearance and demethylation clearance (formation of desmethylcitalopram) were significantly lower in poor metabolizers of Mephenytoin compared to extensive metabolizers (median 15.2 vs. 27.3 and 2.6 vs. 5.9 L/h, respectively). It was further indicated that the demethylation of desmethylcitalopram to didesmethylcitalopram depends on the sparteine oxygenase CYP2D6. Didesmethylcitalopram could virtually not be detected in any poor metabolizers of sparteine, contrasting measurable serum levels in all sparteine/Mephenytoin extensive metabolizers. The demethylation clearance of desmethylcitalopram was significantly lower in sparteine poor metabolizers compared to extensive metabolizers (0.3 vs. 2.4 L/h, respectively). During administration of citalopram, there was a modest increase in sparteine metabolic ratio from median 0.31 to 0.80 in extensive metabolizers of sparteine, whereas the Mephenytoin S/R ratio was unaltered during citalopram treatment. Both the sparteine and the Mephenytoin oxidation polymorphism thus appear to contribute partially to the total pharmacokinetic variability of citalopram.

Joyce A Goldstein - One of the best experts on this subject based on the ideXlab platform.

  • identification of human cyp2c19 residues that confer s Mephenytoin 4 hydroxylation activity to cyp2c9
    Biochemistry, 2001
    Co-Authors: Chengchung Tsao, Michael R Wester, Burhan I Ghanayem, Sherry J Coulter, Brian Chanas, Eric F Johnson, Joyce A Goldstein
    Abstract:

    CYP2C19 is selective for the 4‘-hydroxylation of S-Mephenytoin while the highly similar CYP2C9 has little activity toward this substrate. To identify critical amino acids determining the specificity of human CYP2C19 for S-Mephenytoin 4‘-hydroxylation, we constructed chimeras by replacing portions of CYP2C9 containing various proposed substrate recognition sites (SRSs) with those of CYP2C19 and mutating individual residues by site-directed mutagenesis. Only a chimera containing regions encompassing SRSs 1−4 was active (30% of wild-type CYP2C19), indicating that multiple regions are necessary to confer specificity for S-Mephenytoin. Mutagenesis studies identified six residues in three topological components of the proteins required to convert CYP2C9 to an S-Mephenytoin 4‘-hydroxylase (6% of the activity of wild-type CYP2C19). Of these, only the I99H difference located in SRS 1 between helices B and C reflects a change in a side chain that is predicted to be in the substrate-binding cavity formed above the h...

  • a novel transversion in the intron 5 donor splice junction of cyp2c19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug s Mephenytoin
    Journal of Pharmacology and Experimental Therapeutics, 1999
    Co-Authors: Gordon C Ibeanu, Kim Brosen, P Dayer, Grant R Wilkinson, Burhan I Ghanayem, Joyce A Blaisdell, Ronald J Ferguson, Simone Benhamou, Christine Bouchardy, Joyce A Goldstein
    Abstract:

    Cytochrome P-450 (CYP) 2C19 is responsible for the metabolism of a number of therapeutic agents such as S -Mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Genetic polymorphisms in this enzyme are responsible for the poor metabolizers (PM) of Mephenytoin, which represent ∼13–23% of Asians and 3–5% of Caucasians. Several polymorphisms contribute to this phenotype. We have isolated two new allelic variants that contribute to the PM phenotype in Caucasians. CYP2C19*7 contained a single T → A nucleotide transversion in the invariant GT at the 5′ donor splice site of intron 5. The second PM allele , CYP2C19*8, consisted of a T358C nucleotide transition in exon 3 that results in a Trp120Arg substitution. In a bacterial expression system, CYP2C198 protein exhibited a dramatic (∼90% and 70%) reduction in the metabolism of S -Mephenytoin and tolbutamide, respectively, when compared with the wild-type CYP2C191B protein. Restriction fragment length polymerase chain reaction tests were developed to identify the new allelic variants.

  • genetic tests which identify the principal defects in cyp2c19 responsible for the polymorphism in Mephenytoin metabolism
    Methods in Enzymology, 1996
    Co-Authors: Joyce A Goldstein, Joyce Blaisdell
    Abstract:

    Publisher Summary This chapter describes the genetic tests that identify the principal defects in CYP2C19 responsible for the polymorphism in Mephenytoin metabolism. A genetic polymorphism in the metabolism of the anticonvulsant drug S-Mephenytoin has been studied extensively in humans. This polymorphism also affects the metabolism of a number of other clinically used drugs, including omeprazole, proguanil, citalopram, barbiturates, and, somewhat to a smaller extent, that of propranolol, certain tricyclic antidepressants, and diazepam. The enzyme responsible for the metabolism of Mephenytoin has been identified as CYP2C19. Individuals can be divided into two phenotypes, extensive metabolizers (EMs) and poor metabolizers (PMs) of Mephenytoin. The two principal genetic defects in CYP2C19 responsible for the poor metabolizers (PMs) phenotype in humans have been identified. The primary defect producing the PM phenotype is a single G →A base pair mutation in exon 5 of CYP2C19 (CYP2C19 m1 ) that produces an aberrant splice site. The second major mutation (CYP2C19 m2 ) was identified consisting of a G →A mutation of exon 4 of CYP2C19 that creates a premature stop codon. The chapter describes the PCR-restriction tests for the detection of CYP2C19ml and CYP2C19m2.

  • genetic analysis of the s Mephenytoin polymorphism in a chinese population
    Clinical Pharmacology & Therapeutics, 1995
    Co-Authors: Sonia M F De Morais, Joyce A Goldstein, Songling Huang, Yiqing Lu, Zhousheng Xiao, Hong-hao Zhou
    Abstract:

    The 4'-hydroxylation of S-Mephenytoin exhibits a polymorphism in humans, with the poor metabolizer phenotype exhibiting a lower frequency in white (3% to 5%) than in Oriental populations (13% to 23%). Two mutations in CYP2C19 (CYP2C19m1 and CYP2C19m2) have recently been described that account for ~85% of white and 100% of Japanese poor metabolizers. This study examines whether these mutations account for the poor metabolizer phenotype in the Chinese population. The metabolism of S-Mephenytoin exhibited a bimodal distribution in 244 unrelated Chinese subjects, although the distribution of the two phenotypes overlapped. In 75 selected Chinese subjects, CYP2C19 genotype analysis predicted the phenotype with 100% accuracy. The frequency of the poor metabolizer phenotype was ~11% (95% confidence interval 7% to 15%). The frequency of the CYP2C19m1 allele was 0.289, whereas that of CYP2C19m2 was 0.044. Homozygous extensive metabolizers had slightly lower ratios of SR-Mephenytoin compared with heterozygous extensive metabolizers, showing a gene-dosage effect. These data show the advantages of genotype analysis in investigations of the Mephenytoin phenotype in Oriental subjects. Clinical Pharmacology & Therapeutics (1995) 58, 404–411; doi:

  • the hydroxylation of omeprazole correlates with s Mephenytoin metabolism a population study
    Clinical Pharmacology & Therapeutics, 1995
    Co-Authors: John D Balian, Nadia Sukhova, James W Harris, Jan Hewett, Linda W Pickle, Joyce A Goldstein, Raymond L Woosley, David A Flockhart
    Abstract:

    We compared omeprazole and Mephenytoin as probes for the CYP2C19 metabolic polymorphism. Single oral doses of omeprazole (20 mg) or Mephenytoin (100 mg) were administered at least 1 week apart to 167 healthy volunteers. Mephenytoin metabolism was measured using the amount of 4′-hydroxyMephenytoin and the S/R ratio of Mephenytoin in an 8-hour urine collection. Omeprazole hydroxylation was measured using the ratio of omeprazole to 5′-hydroxyomeprazole in serum 2 hours after dosing. All three methods separated poor- or extensive-metabolizer phenotypes with complete concordance. Omeprazole hydroxylation correlated with the S/R ratio of Mephenytoin in extensive metabolizers (r2 = 0.681; p < 0.001). Genotyping tests showed that six poor metabolizers of omeprazole were homozygous for a single base pair mutation in exon 5 of CYP2C19. These results support the hypothesis that omeprazole 5′-hydroxylation cosegregates with the CYP2C19 metabolic polymorphism. Clinical Pharmacology & Therapeutics (1995) 57, 662–669; doi: