Effects of Major Transporter and Metabolizing Enzyme Gene Polymorphisms on Carbamazepine Metabolism in Chinese Patients with Epilepsy

Zhu, Xu; Yun, Wenting; Sun, Xiaofu; Qiu, Feng; Zhao, Limei; Guo, Yingjie

doi:10.2217/pgs.14.142

Cited by 38 publications

(31 citation statements)

References 51 publications

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“…In 84 Chinese patients, lower trough concentration (C 0 ) values in those with the 3435TT genotype were reported [190]. A recent study in 210 Chinese patients showed that 3435CT carriers had lower C 0 /D values [191]. A lower response rate in carriers of the 2677TT genotype was reported [192], whereas 3435TT had no significant effect [193].…”

Section: Antiepileptic Drugsmentioning

confidence: 99%

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

et al. 2015

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ATP-binding cassette transporter B1 (ABCB1; P-glycoprotein; multidrug resistance protein 1) is an adenosine triphosphate (ATP)-dependent efflux transporter located in the plasma membrane of many different cell types. Numerous structurally unrelated compounds, including drugs and environmental toxins, have been identified as substrates. ABCB1 limits the absorption of xenobiotics from the gut lumen, protects sensitive tissues (e.g. the brain, fetus and testes) from xenobiotics and is involved in biliary and renal secretion of its substrates. In recent years, a large number of polymorphisms of the ABCB1 [ATP-binding cassette, sub-family B (MDR/TAP), member 1] gene have been described. The variants 1236C>T (rs1128503, p.G412G), 2677G>T/A (rs2032582, p.A893S/T) and 3435C>T (rs1045642, p.I1145I) occur at high allele frequencies and create a common haplotype; therefore, they have been most widely studied. This review provides an overview of clinical studies published between 2002 and March 2015. In summary, the effect of ABCB1 variation on P-glycoprotein expression (messenger RNA and protein expression) and/or activity in various tissues (e.g. the liver, gut and heart) appears to be small. Although polymorphisms and haplotypes of ABCB1 have been associated with alterations in drug disposition and drug response, including adverse events with various ABCB1 substrates in different ethnic populations, the results have been majorly conflicting, with limited clinical relevance. Future research activities are warranted, considering a deep-sequencing approach, as well as well-designed clinical studies with appropriate sample sizes to elucidate the impact of rare ABCB1 variants and their potential consequences for effect sizes.

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Section: Antiepileptic Drugsmentioning

confidence: 99%

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

et al. 2015

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“…Furthermore, evidence of microsomal epoxide hydrolase activity at or near the blood-brain barrier has been reported (Ghersi-Egea et al, 1994). Carbamazepine, phenobarbital, and phenytoin are three xenobiotics with well characterized metabolic pathways involving epoxide hydrolase, with recent evidence suggesting that single nucleotide polymorphisms in the microsomal epoxide hydrolase gene EPHX1 influence carbamazepine exposure in vivo (El-Sherbeni and El-Kadi, 2014;Zhu et al, 2014;Daci et al, 2015).…”

Section: Epoxide Hydrolasesmentioning

confidence: 99%

Cytochrome P450 and Non-Cytochrome P450 Oxidative Metabolism: Contributions to the Pharmacokinetics, Safety, and Efficacy of Xenobiotics

Foti

Dalvie

2016

Drug Metabolism and Disposition

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The drug-metabolizing enzymes that contribute to the metabolism or bioactivation of a drug play a crucial role in defining the absorption, distribution, metabolism, and excretion properties of that drug. Although the overall effect of the cytochrome P450 (P450) family of drug-metabolizing enzymes in this capacity cannot be understated, advancements in the field of non-P450-mediated metabolism have garnered increasing attention in recent years. This is perhaps a direct result of our ability to systematically avoid P450 liabilities by introducing chemical moieties that are not susceptible to P450 metabolism but, as a result, may introduce key pharmacophores for other drug-metabolizing enzymes. Furthermore, the effects of both P450 and non-P450 metabolism at a drug's site of therapeutic action have also been subject to increased scrutiny. To this end, this Special Section on Emerging Novel Enzyme Pathways in Drug Metabolism will highlight a number of advancements that have recently been reported. The included articles support the important role of non-P450 enzymes in the clearance pathways of U.S. Food and Drug Administration-approved drugs over the past 10 years. Specific examples will detail recent reports of aldehyde oxidase, flavin-containing monooxygenase, and other non-P450 pathways that contribute to the metabolic, pharmacokinetic, or pharmacodynamic properties of xenobiotic compounds. Collectively, this series of articles provides additional support for the role of non-P450-mediated metabolic pathways that contribute to the absorption, distribution, metabolism, and excretion properties of current xenobiotics.

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“…Carbamazepine (CBZ), a first-line antiepileptic drug, has been widely prescribed for the treatment of partial and generalized tonic-clonic seizures. It has been reported that CYP3A5*3 is associated with CBZ pharmacokinetics in Japanese [ 20 ], Korean [ 21 ], and Chinese [ 22 ] epileptic patients, and that CYP3A5 expressers are more likely to require higher CBZ maintenance doses than nonexpressers (GA + AA vs. GG). The CYP3A5 genotype may also have dose-dependent effects on ABT-773 plasma levels.…”

Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms of pharmacogenomic VIP variants in the Uygur population from northwestern China

et al. 2015

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BackgroundDrug response variability observed amongst patients is caused by the interaction of both genetic and non-genetic factors, and frequencies of functional genetic variants are known to vary amongst populations. Pharmacogenomic research has the potential to help with individualized treatments. We have not found any pharmacogenomics information regarding Uygur ethnic group in northwest China. In the present study, we genotyped 85 very important pharmacogenetic (VIP) variants (selected from the PharmGKB database) in the Uygur population and compared our data with other eleven populations from the HapMap data set.ResultsThrough statistical analysis, we found that CYP3A5 rs776746, VKORC1 rs9934438, and VKORC1 rs7294 were most different in Uygur compared with most of the eleven populations from the HapMap data set. Compared with East Asia populations, allele A of rs776746 is less frequent and allele A of rs7294 is more frequent in the Uygur population. The analysis of F-statistics (Fst) and population structure shows that the genetic background of Uygur is relatively close to that of MEX.ConclusionsOur results show significant differences amongst Chinese populations that will help clinicians triage patients for better individualized treatments.

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Effects of Major Transporter and Metabolizing Enzyme Gene Polymorphisms on Carbamazepine Metabolism in Chinese Patients with Epilepsy

Abstract: Our data suggest that certain polymorphisms of major transporter and metabolizing enzyme genes could in part influence interindividual variability of CBZ metabolism in Chinese patients with epilepsy.

Cited by 38 publications

References 51 publications

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

Cytochrome P450 and Non-Cytochrome P450 Oxidative Metabolism: Contributions to the Pharmacokinetics, Safety, and Efficacy of Xenobiotics

Genetic polymorphisms of pharmacogenomic VIP variants in the Uygur population from northwestern China

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