The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients

Schenk, Paul W.; Vliet, Martin van; Mathôt, Ron A. A.; Gelder, Teun van; Vulto, Arnold G.; Fessem, M A C van; Rij, S Verploegh-Van; Lindemans, Jan; Bruijn, Jan A.; Schaik, Ron H.N. van

doi:10.1038/tpj.2009.50

Cited by 37 publications

(21 citation statements)

References 25 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The 2C19*17 allele has been reported to be associated with increased enzyme activity, i.e., extensive metabolizer (EM) and accordingly lower plasma concentrations of imipramine and other drugs (Li-Wan-Po et al, 2010) (Schenk et al, 2010). We found a trend of gene-dose effect of 2C19*17 allele on the plasma AUC 0–48h of DA in human subjects (Fig.…”

Section: Resultsmentioning

confidence: 99%

Cytochrome P450 Isoforms in the Metabolism of Decursin and Decursinol Angelate from Korean Angelica

Zhang

Tang

et al. 2015

Am. J. Chin. Med.

View full text Add to dashboard Cite

We have shown that the in vitro hepatic microsomal metabolism of pyranocoumarin compound decursinol angelate (DA) to decursinol (DOH) exclusively requires cytochrome P450 enzymes (CYP) whereas the conversion of its isomer decursin (D) to DOH can be mediated by CYP and esterase(s). To provide insight into specific isoforms involved, here we show with recombinant human CYP that 2C19 was the most active at metabolizing D and DA in vitro followed by 3A4. With carboxylesterases (CES), D was hydrolyzed by CES2 but not CES1, and DA was resistant to both CES1 and CES2. In human liver microsomal preparation, general CYP inhibitor 1-aminobenzotriazole (ABT) and respective competitive inhibitors for 2C19 and 3A4, (+)-N-3-benzylnirvanol and ketoconazole, substantially retarded the metabolism of DA and, to a lesser extent, of D. In healthy human subjects from a single-dose pharmacokinetic study, 2C19 extensive metabolizer genotype (2C19*17 allele) tended to have less plasma DA AUC0–48h and poor metabolizer genotype (2C19*2 allele) tended to have greater DA AUC0–48h. In mice given a single dose of D/DA, pretreatment with ABT boosted the plasma and prostate levels of D and DA by more than an order of magnitude. Taken together, our findings suggest that CYP isoforms 2C19 and 3A4 may play a crucial role in the first pass liver metabolism of DA and, to a lesser extent, that of D in humans. Pharmacogenetics with respect to CYP genotypes and interactions among CYP inhibitor drugs and D/DA should therefore be considered in designing future translation studies of DA and/or D.

show abstract

Section: Resultsmentioning

confidence: 99%

Cytochrome P450 Isoforms in the Metabolism of Decursin and Decursinol Angelate from Korean Angelica

Zhang

Tang

et al. 2015

Am. J. Chin. Med.

View full text Add to dashboard Cite

show abstract

“…With regard to UMs, CYP2C19*17 has been found to correlate with lower serum concentrations of several antidepressants compared with EM patients [40,89,90]; however, the exact clinical relevance of UM genotypes in antidepressant response warrants further investigation.…”

Section: Cyp2c19 Genotype and Drug Responsementioning

confidence: 99%

PharmGKB summary

Scott¹,

Sangkuhl²,

Shuldiner

et al. 2012

Pharmacogenetics and Genomics

147

View full text Add to dashboard Cite

show abstract

“…10 In Asian populations, the allele frequency of the CYP2C19*17 allele is approximately 6% and the CYP2C19*2 allelic variant has a frequency of about 30%. 18 CYP2C19 polymorphism impacts not only drug plasma levels, 19, 20, 21 but also the therapeutic outcome of psychotropic drugs. 22 …”

Section: Introductionmentioning

confidence: 99%

Decreased hippocampal volume and increased anxiety in a transgenic mouse model expressing the human CYP2C19 gene

et al. 2013

View full text Add to dashboard Cite

Selective serotonin reuptake inhibitors, tricyclic antidepressants, various psychoactive drugs, as well as endogenous steroids and cannabinoid-like compounds are metabolized by the polymorphic cytochrome P450 2C19 (CYP2C19). Absence of this enzyme has been recently shown to associate with lower levels of depressive symptoms in human subjects. To investigate endogenous functions of CYP2C19 and its potential role in brain function, we have used a transgenic mouse model carrying the human CYP2C19 gene. Here, CYP2C19 was expressed in the developing fetal, but not adult brain and was associated with altered fetal brain morphology, where mice homozygous for the CYP2C19 transgenic insert had severely underdeveloped hippocampus and complete callosal agenesis and high neonatal lethality. CYP2C19 expression was also found in human fetal brain. In adult hemizygous mice we observed besides decreased hippocampal volume, an altered neuronal composition in the hippocampal dentate gyrus. Reduced hippocampal volumes have been reported in several psychiatric disorders, supporting the relevance of this model. Here we found that adult hemizygous CYP2C19 transgenic mice demonstrate behavior indicative of increased stress and anxiety based on four different tests. We hypothesize that expression of the CYP2C19 enzyme prenatally may affect brain development by metabolizing endogenous compounds influencing this development. Furthermore, CYP2C19 polymorphism may have a role in interindividual susceptibility for psychiatric disorders.

show abstract

The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients

Cited by 37 publications

References 25 publications

Cytochrome P450 Isoforms in the Metabolism of Decursin and Decursinol Angelate from Korean Angelica

Cytochrome P450 Isoforms in the Metabolism of Decursin and Decursinol Angelate from Korean Angelica

PharmGKB summary

Decreased hippocampal volume and increased anxiety in a transgenic mouse model expressing the human CYP2C19 gene

Contact Info

Product

Resources

About