Hepatic CYP2B6 Expression: Gender and Ethnic Differences and Relationship to<i>CYP2B6</i>Genotype and CAR (Constitutive Androstane Receptor) Expression

Lamba, Vishal; Lamba, Jatinder K.; Yasuda, Kazuto; Strom, Stephen C.; Dávila, Julio C.; Hancock, Michael L.; Fackenthal, James D.; Rogan, Peter K.; Ring, Barbara J.; Wrighton, Steven; Schuetz, Erin G.

doi:10.1124/jpet.103.054866

Cited by 366 publications

(373 citation statements)

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“…Hepatic CYP2B6, whose substrates include the alkylating agents cyclophosphamide and ifosfamide, is expressed differently between the sexes. 19 Significantly higher amounts of CYP2B6 mRNA protein and enzyme activity were found in females than in males. As a consequence some agents will be more effective in females and may, at the same time, show more toxicity.…”

Section: Discussionmentioning

confidence: 96%

“…As a consequence some agents will be more effective in females and may, at the same time, show more toxicity. 18,19 It is of interest that in our trials women responded significantly better than men (Table 2) although they experienced more toxicity, particularly gastro-intestinal toxicity, and were thus less likely to have received the full dose of treatment.Although our trials did not include treatment with monoclonal antibodies, recent pharmacokinetic data showed that the clearance of rituximab is reduced and its elimination half-life more prolonged in women than in men. 20 Higher rituximab serum concentrations before next therapy and higher response rates were associated, in another pharmacokinetic study, 21 with female sex.…”

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The clinical significance of patients' sex in chronic lymphocytic leukemia

Catovsky¹,

Wade

Else³

2014

Haematologica

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© F e r r a t a S t o r t i F o u n d a t i o nwhere. 2,9,10 Briefly, chlorambucil was one of the arms in every trial. 11The comparators were the combination of COP (cyclophosphamide, oncovin and prednisolone) and splenic irradiation in CLL1, chlorambucil plus prednisolone and splenic irradiation in CLL2, chlorambucil plus epirubicin in CLL3, and fludarabine with or without cyclophosphamide in LRF CLL4. Biological, cytogenetic and molecular markers were available from patients entered in the LRF CLL4 trial and have been reported elsewhere, together with a full description of the cutoffs used to define positivity. 12,13 Causes of death were centrally categorized using the patients' death certificates and/or reports from the participating centers. Follow-up (overall survival only) was to June 2012 for the trials and June 2010 for the registration series, with a median follow-up for each trial of at least 9 years.Statistical analyses used the chi square test for comparisons of incidence, response to therapy and toxicities. Kaplan-Meier survival curves were calculated and compared by the log-rank test. Overall survival was calculated from randomization to death from any cause. Progression-free survival in the LRF CLL4 trial was defined as the time from randomization to relapse needing further treatment, progression, or death from any cause. For non-responders and progressive disease, date of progression was when no response or progressive disease was recorded. Multivariate analyses of variables significantly associated with response and overall survival in univariate tests were performed by means of stepwise generalized linear modeling and the Cox proportional hazards model respectively. Values of P≤0.05 (two sided) were considered statistically significant. Analyses were performed using the STA-TISTICA software from StatSoft, a wholly owned subsidiary of Dell, Inc.The LRF CLL4 trial was registered as an International Standard Randomized Trial, number ISRCTN58585610 and was approved by the UK multicenter research ethics committee (MREC). All four trials followed the UK Medical Research Council guidelines for good clinical practice. All patients provided informed consent. All authors had access to the primary clinical trial data. The main trial endpoints have been previously reported. 2,9,10 ResultsThe main characteristics of the patients in both series are shown in Table 1. The proportion of females was significantly higher in the registration series than in the randomized series. Women were more likely than men to be aged ≥70 years in both series. They were more likely to have Binet stage A-progressive disease than stage B or C in the randomized series and slightly more likely to have Rai stage 0 disease than Rai stages I-II in the registration series.Overall survival was significantly longer in women both in the randomized series [hazard ratio (HR): 0.72, 95% confidence interval (CI): 0.64-0.81, P<0.0001; Figure 2A Figure 2B). At 10 years, the overall survival rate in the randomized series was 27% (95% CI...

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Section: Discussionmentioning

confidence: 96%

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confidence: 86%

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The clinical significance of patients' sex in chronic lymphocytic leukemia

Catovsky¹,

Wade

Else³

2014

Haematologica

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“…In another study, Xie et al showed that the CYP2B6*6 variant enhanced cyclophosphamide hydroxylation [34]. Lamba et al evaluated CYP2B6 splicing variants in human liver samples and demonstrated that the CYP2B6-G516T, -C1459T, and intron 3 C15582T genotypes were predictors of hepatic CYP2B6 activity and varied according to sex and ethnicity [35]. In an additional study by Desta et al, bupropion protein expression and activity, and EFV hydroxylation were significantly decreased in subjects with the CYP2B6*5, or CYP2B6*6 [26].…”

Section: Cyp2b6 Gene Polymorphisms and Hepatic Cyp2b6 Expression And mentioning

confidence: 99%

Effect of Host Genetic Variation on the Pharmacokinetics and Clinical Response of Nnrtis

Saitoh

Spector

2007

Future HIV Ther.

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Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been used widely for treating human immunodeficiency virus type 1 (HIV-1) infected patients as a component of highly active antiretroviral therapy (HAART) and for the prevention of mother-to-child transmission (MTCT). Cytochrome P450 (CYP) 2B6 is an important hepatic isoenzyme responsible for the metabolism of NNRTIs including efavirenz and nevirapine. Recent pharmacogenetic studies have shown that CYP2B6 genetic variants alter hepatic CYP2B6 protein expression and function, and the pharmacokinetics of several CYP2B6 substrates. In particular, the CYP2B6-G516T polymorphism in exon 4 affects the pharmacokinetics of efavirenz. Other studies have shown associations of the CYP2B6-G516T genotype with nevirapine pharmacokinetics and central nervous system adverse effects related to efavirenz use. In total, CYP2B6 genetic variants are important determinants of efavirenz and nevirapine pharmacokinetics . Further studies are needed to identify the associations of CYP2B6 genetic variants with the development of NNRTI resistant viruses.

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“…30 Alleles that carry polymorphisms 415A4G, 516G4T, 136A4G, 296G4A, 785A4G, 419G4A, and 1172T4A have all been associated with differences in the expression of the encoded proteins. [31][32][33] The relevance of CYP2B6 polymorphisms on EFV metabolism has been extensively analysed. Haas et al assessed the impact of the 526G4T polymorphism on EFV clearance Figure 2 Metabolic pathway for Efavirenz.…”

Section: Non-nucleoside Reverse Transcriptase Inhibitorsmentioning

confidence: 99%

Overview of the pharmacogenetics of HIV therapy

Rodrı́guez-Nóvoa

Barreiro²,

Jiménez-Nácher

et al. 2006

Pharmacogenomics J

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The administration of standard doses of most antiretroviral drugs results in significant variations in plasma drug concentrations among different individuals, influencing antiviral activity as well as incidence of drug-related toxicities. The reasons for this large inter-individual variability in drug levels are multifactorial, and involve differences in metabolism related to gender, concomitant medications, drug compliance, underlying diseases and genetic factors. Pharmacogenetics is the discipline that analyses the genetic basis for the inter-individual variation in the body disposition of drugs. One of its main goals is to give grounds to individualized treatment. The majority of pharmacogenetic traits so far have involved drug metabolism. This is the case for the inherited variation in the pharmacokinetics and pharmacodynamics of drugs such as hydralazine or isoniazid, which is due to polymorphisms in the N-acetyltransferase-2 (NAT2) gene, which allows splitting the population into three categories: slow, intermediate, and fast metabolizers. Pharmacogenetic studies conducted so far with antiretroviral drugs have focussed on metabolizer enzymes at the liver and on transporter proteins on cell membranes. Herein, we review the most relevant metabolizer enzymes and protein transporters, along with the genetic polymorphisms, which seem to influence the pharmacokinetics of antiretroviral drugs, ultimately determining its efficacy and toxicity.

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Hepatic CYP2B6 Expression: Gender and Ethnic Differences and Relationship toCYP2B6Genotype and CAR (Constitutive Androstane Receptor) Expression

Cited by 366 publications

References 32 publications

The clinical significance of patients' sex in chronic lymphocytic leukemia

The clinical significance of patients' sex in chronic lymphocytic leukemia

Effect of Host Genetic Variation on the Pharmacokinetics and Clinical Response of Nnrtis

Overview of the pharmacogenetics of HIV therapy

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