<i>O-</i>Dealkylation of Fluoxetine in Relation to<i>CYP2C19</i>Gene Dose and Involvement of CYP3A4 in Human Liver Microsomes

Liu, Zhao‐Qian; Zhu, Bing; Tan, Yun-Fu; Tan, Zhi‐Rong; Wang, Liansheng; Huang, Shiyang; Shu, Yan; Zhou, Hong‐Hao

doi:10.1124/jpet.300.1.105

Cited by 17 publications

(8 citation statements)

References 21 publications

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“…Like Contin et al (2002), we observed that subjects carrying one CYP2C19*2 allele had NCLB/ CLB plasma concentration ratios higher than subjects with no mutant allele, suggesting a gene-dosage effect with CYP2C19. This result was in accordance with previous published works on other CYP2C19 substrates such as diazepam (Qin et al,1999), omeprazole (Lamba et al,2001), fluoxetine (Liu et al, 2002), or carisoprodol (Bramness et al, 2003).…”

Section: Discussionsupporting

confidence: 93%

In Vitro Characterization of Clobazam Metabolism by Recombinant Cytochrome P450 Enzymes: Importance of Cyp2c19

Giraud¹,

Tran²,

Rey³

et al. 2004

Drug Metab Dispos

105

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The specific cytochrome P450 (P450) isoforms mediating the biotransformations of clobazam (CLB) and those of its major metabolites, N-desmethylclobazam (NCLB) and 4-hydroxyclobazam were identified using cDNA-expressed P450 and P450-specific chemical inhibitors. Among the 13 cDNA-expressed P450 isoforms tested, CLB was mainly demethylated by CYP3A4, CYP2C19, and CYP2B6 and 4-hydroxylated by CYP2C19 and CYP2C18. CYP2C19 and CYP2C18 catalyzed the 4-hydroxylation of NCLB. The kinetics of the major biotransformations were studied: CYP3A4, CYP2C19, and CYP2B6 mediated the formation of NCLB with K m ‫؍‬ 29.0, 31.9, and 289 M, V max ‫؍‬ 6.20, 1.15, and 5.70 nmol/min/nmol P450, and intrinsic clearance (CL int ) ‫؍‬ 214, 36.1, and 19.7 l/min/nmol P450, respectively. NCLB was hydroxylated to 4-hydroxydesmethylclobazam by CYP2C19 with K m ‫؍‬ 5.74 M, V max ‫؍‬ 0.219 nmol/min/ nmol P450, and CL int ‫؍‬ 38.2 l/min/nmol P450 (Hill coefficient ‫؍‬ 1.54). These findings were supported by chemical inhibition studies in human liver microsomes. Indeed, ketoconazole (1 M) inhibited the demethylation of CLB by 70% and omeprazole (10 M) by 19%; omeprazole inhibited the hydroxylation of NCLB by 26%. Twentytwo epileptic patients treated with CLB were genotyped for CYP2C19. The NCLB/CLB plasma metabolic ratio was significantly higher in the subjects carrying one CYP2C19*2 mutated allele than in those carrying the wild-type genotype. CYP3A4 and CYP2C19 are the main P450s involved in clobazam metabolism. Interactions with other drugs metabolized by these P450s can occur; moreover, the CYP2C19 genetic polymorphism could be responsible for interindividual variations of plasma concentrations of N-desmethylclobazam and thus for occurrence of adverse events. Materials and MethodsChemicals and Reagents. Clobazam and N-desmethylclobazam were obtained from Laboratoires Roussel-Uclaf/Sanofi-Synthelabo France (Paris, France). 4Ј-Hydroxyclobazam and 4Ј-hydroxy-N-desmethylclobazam were synthesized and kindly provided by Laboratoires Biocodex (Montrouge, France).

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Section: Discussionsupporting

confidence: 93%

In Vitro Characterization of Clobazam Metabolism by Recombinant Cytochrome P450 Enzymes: Importance of Cyp2c19

Giraud¹,

Tran²,

Rey³

et al. 2004

Drug Metab Dispos

105

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“…We were unable to obtain evidence for an influence of the CYP2C19 genotype on fluoxetine or norfluoxetine plasma concentrations. A contribution of CYP2C19 in the conversion of fluoxetine to norfluoxetine has been supported by in vitro experiments (Liu et al 2001a & 2002) and an in vivo study conducted in 14 healthy men, 6 of whom had poor metabolizer status for CYP2C19 activity (Liu et al 2001b). The latter study was performed in Chinese volunteers after single dose administration.…”

Section: Discussionmentioning

confidence: 96%

“…Evidence from in vitro (Stevens & Wrighton 1993; Margolis et al 2000; Ring et al 2001; Liu et al 2001a & 2002) and in vivo (Hamelin et al 1996; Fjordside et al 1999; Eap et al 2001; Liu et al 2001b; Charlier et al 2003; Llerena et al 2004) studies indicates that the metabolism of fluoxetine and norfluoxetine is catalyzed, at least in part, by the cytochrome P450 (CYP) isoenzymes CYP2D6, CYP2C19, CYP2C9 and CYP3A4. Of these enzymes, the former three exhibit genetic polymorphism.…”

mentioning

confidence: 99%

Influence of CYP2C9, 2C19 and 2D6 Genetic Polymorphisms on the Steady‐State Plasma Concentrations of the Enantiomers of Fluoxetine and Norfluoxetine

Scordo

Spina

et al. 2005

Basic Clin Pharma Tox

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Abstract:The antidepressant fluoxetine is administered as racemic mixture of two enantiomers (S-and R-fluoxetine). While S-and R-fluoxetine are equipotent in blocking serotonin reuptake, the enantiomers of the demethylated metabolite, norfluoxetine, show marked differences in pharmacological activity, S-norfluoxetine being about 20 times as potent as Rnorfluoxetine as a serotonin reuptake inhibitor. In vitro and in vivo data suggest that the metabolism of fluoxetine to norfluoxetine is stereoselective and mediated, at least in part, by the polymorphic cytochrome P450 (CYP) isoenzymes CYP2D6, CYP2C9 and CYP2C19. In the present study, the influence of CYP2D6, CYP2C9 and CYP2C19 polymorphisms on the steady-state plasma concentrations of fluoxetine and norfluoxetine enantiomers was evaluated in 78 patients receiving chronic fluoxetine treatment (10-60 mg/day). The plasma concentrations of fluoxetine and norfluoxetine enantiomers were measured and CYP2D6, CYP2C9 and CYP2C19 genotypes were analyzed. No statistically significant relationship was identified between CYP2D6 or CYP2C19 genotypes and the dose normalised plasma concentrations of any of the enantiomers or the active moiety (i.e. the sum of S-fluoxetine, R-fluoxetine and S-norfluoxetine). However, the plasma concentration of S-norfluoxetine was very low in the only CYP2D6 poor metaboliser. Furthermore, the median S-norfluoxetine/S-fluoxetine ratios were higher in homozygous than in heterozygous extensive metabolisers (PϽ0.05). Among homozygous extensive metabolizers for CYP2D6, patients homozygous for CYP2C9*1 had lower dose-normalized Rfluoxetine concentrations and lower active moiety levels compared with those carrying detrimental CYP2C9 alleles (PϽ0.05). These results suggest that CYP2D6 and CYP2C9 polymorphisms contribute to the interindividual variability in fluoxetine pharmacokinetics at steady-state.Fluoxetine is one of the most widely prescribed selective serotonin reuptake inhibitors. Apart from its use in depression, it is also used for the treatment of a variety of other psychiatric and medical conditions, in which serotonin is thought to play a role (Gram 1994;Stokes & Holtz 1997). The commercially available drug is a racemic mixture of two enantiomers (S-and R-fluoxetine), which are approximately equipotent in blocking serotonin reuptake (Wong et al. 1985). Conversely, the enantiomers of the main demethylated metabolite, norfluoxetine, which are present in the circulation at higher concentrations than those of the parent drug, show marked differences in pharmacological activity, S-norfluoxetine being about 20 times more potent than R-norfluoxetine as a serotonin reuptake inhibitor both in vitro and in vivo (Fuller et al. 1992;Wong et al. 1993).

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“…Patients often respond to drugs differently because of polymorphisms in their drug-metabolizing enzymes [10]. The importance of membrane drug transporters in determining the variability of drug response is beginning to be recognized [11].…”

Section: Introductionmentioning

confidence: 99%

Characterization and analyses of multidrug resistance-associated protein 1 (MRP1/ABCC1) polymorphisms in Chinese population

Yin

Huang

Yang

et al. 2009

Pharmacogenetics and Genomics

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Multidrug resistance (MDR) is one of the major obstacles for successful cancer chemotherapy. Over-expression of ATP-binding cassette (ABC) transporters such as MRP1/ABCC1 has been suggested to cause MDR. In this study, we explored the distribution frequencies of four common single nucleotide polymorphisms (SNPs) of MRP1/ABCC1 in a mainland Chinese population and investigated whether these SNPs affect the expression and function of the MRP1/ABCC1. We found that the allelic frequencies of Cys43Ser (128G>C), Thr73Ile (218C>T), Arg723Gln (2168G>A) and Arg1058Gln (3173G>A) in mainland Chinese were 0.5%, 1.4%, 5.8% and 0.5%, respectively. These four SNPs were recreated by site-directed mutagenesis and tested for their effect on MRP1/ABCC1 expression and MDR function in HEK293 and CHO-K1 cells lines. We found that none of these mutations had any effect on MRP1/ABCC1 expression and trafficking, but that Arg723Gln mutation significantly reduced MRP1/ABCC1-mediated resistance to daunorubicin, doxorubicin, etoposide, vinblastine and vincristine. The Cys43Ser mutation did not affect all tested drugs resistance. On the other hand, the Thr73Ile mutation reduced resistance to methotrexate and etoposide while the Arg1058Gln mutation increased the response of two anthracycline drugs and etoposide in HEK293 and CHO-K1 cells as well as vinblastine and methotrexate in CHO-K1 cells. We conclude that the allelic frequency of the Arg723Gln mutation is relatively higher than other SNPs in mainland Chinese population and therefore this mutation significantly reduces MRP1/ABCC1 activity in MDR.

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O-Dealkylation of Fluoxetine in Relation toCYP2C19Gene Dose and Involvement of CYP3A4 in Human Liver Microsomes

Cited by 17 publications

References 21 publications

In Vitro Characterization of Clobazam Metabolism by Recombinant Cytochrome P450 Enzymes: Importance of Cyp2c19

In Vitro Characterization of Clobazam Metabolism by Recombinant Cytochrome P450 Enzymes: Importance of Cyp2c19

Influence of CYP2C9, 2C19 and 2D6 Genetic Polymorphisms on the Steady‐State Plasma Concentrations of the Enantiomers of Fluoxetine and Norfluoxetine

Characterization and analyses of multidrug resistance-associated protein 1 (MRP1/ABCC1) polymorphisms in Chinese population

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