Proton pump inhibitors (PPIs) are widely used for acid suppression in the treatment and prevention of many conditions, including gastroesophageal reflux disease, gastric and duodenal ulcers, erosive ...esophagitis, Helicobacter pylori infection, and pathological hypersecretory conditions. Most PPIs are metabolized primarily by cytochrome P450 2C19 (CYP2C19) into inactive metabolites, and CYP2C19 genotype has been linked to PPI exposure, efficacy, and adverse effects. We summarize the evidence from the literature and provide therapeutic recommendations for PPI prescribing based on CYP2C19 genotype (updates at www.cpicpgx.org). The potential benefits of using CYP2C19 genotype data to guide PPI therapy include (i) identifying patients with genotypes predictive of lower plasma exposure and prescribing them a higher dose that will increase the likelihood of efficacy, and (ii) identifying patients on chronic therapy with genotypes predictive of higher plasma exposure and prescribing them a decreased dose to minimize the risk of toxicity that is associated with long‐term PPI use, particularly at higher plasma concentrations.
In order to quantitatively predict drug interactions associated with efavirenz-based anti-HIV therapy, we evaluated reversible and time-dependent inhibitions of efavirenz on eight cytochrome P450 ...(CYP) enzymes in vitro. The present study showed that efavirenz was a potent competitive inhibitor of CYP2B6 (average Ki = 1.68 μΜ in HLMs and Ki = 1.38μΜ in expressed CYP2B6) and CYP2C8 (Ki = 4.78 μΜ in pooled HLMs and Ki = 4.80 μΜ in HLMs with CYP2C8*3/*3 genotype). Efavirenz was a moderate inhibitor of CYP2C9 (Ki = 19.46μΜ) and CYP2C19 (Ki = 21.31 μΜ); and a weak inhibitor of CYP3A (Ki = 40.33μΜ). No appreciable inhibition was observed on CYP1A2, CYP2A6 or CYP2D6. No time-dependent inhibition of the CYPs by efavirenz was observed in this study. Quantitative predictions showed that single dose of efavirenz may substantially slow the elimination of drugs predominately cleared by CYP2B6, CYP2C19 or by both enzymes and may also lower the area under the plasma concentration time curve (AUC) of active metabolites of some pro-drugs (e.g., clopidogrel and proguanil) by up to 30%. Depending on substrates, chronic administration of efavirenz may increase the AUC of CYP2C8 and CYP2C9 substrates about 3.5–4.4-fold and 1.7–2.0-fold at steady state.
The HIV type‐1 nonnucleoside reverse transcriptase inhibitor, efavirenz, is widely used to treat HIV type‐1 infection. Efavirenz is predominantly metabolized into inactive metabolites by cytochrome ...P450 (CYP)2B6, and patients with certain CYP2B6 genetic variants may be at increased risk for adverse effects, particularly central nervous system toxicity and treatment discontinuation. We summarize the evidence from the literature and provide therapeutic recommendations for efavirenz prescribing based on CYP2B6 genotypes.
Polypharmacy is common in patients with nonalcoholic fatty liver disease (NAFLD) and previous reports suggest that NAFLD is associated with altered drug disposition. This study aims to determine if ...patients with NAFLD are at risk for altered drug response by characterizing changes in hepatic mRNA expression of genes mediating drug disposition (pharmacogenes) across the histological NAFLD severity spectrum. We utilize RNA-seq for 93 liver biopsies with histologically staged NAFLD Activity Score (NAS), fibrosis stage, and steatohepatitis (NASH). We identify 37 significant pharmacogene-NAFLD severity associations including CYP2C19 downregulation. We chose to validate CYP2C19 due to its actionability in drug prescribing. Meta-analysis of 16 independent studies demonstrate that CYP2C19 is significantly downregulated to 46% in NASH, to 58% in high NAS, and to 43% in severe fibrosis. Our data demonstrate the downregulation of CYP2C19 in NAFLD which supports developing personalized medicine approaches for drugs sensitive to metabolism by the CYP2C19 enzyme.
Efavirenz primary and secondary metabolism was investigated in vitro and in vivo. In human liver microsome (HLM) samples, 7- and 8-hydroxyefavirenz accounted for 22.5 and 77.5% of the overall ...efavirenz metabolism, respectively. Kinetic, inhibition, and correlation analyses in HLM samples and experiments in expressed cytochrome P450 show that CYP2A6 is the principal catalyst of efavirenz 7-hydroxylation. Although CYP2B6 was the main enzyme catalyzing efavirenz 8-hydroxylation, CYP2A6 also seems to contribute. Both 7- and 8-hydroxyefavirenz were further oxidized to novel dihydroxylated metabolite(s) primarily by CYP2B6. These dihydroxylated metabolite(s) were not the same as 8,14-dihydroxyefavirenz, a metabolite that has been suggested to be directly formed via 14-hydroxylation of 8-hydroxyefavirenz, because 8,14-dihydroxyefavirenz was not detected in vitro when efavirenz, 7-, or 8-hydroxyefavirenz were used as substrates. Efavirenz and its primary and secondary metabolites that were identified in vitro were quantified in plasma samples obtained from subjects taking a single 600-mg oral dose of efavirenz. 8,14-Dihydroxyefavirenz was detected and quantified in these plasma samples, suggesting that the glucuronide or the sulfate of 8-hydroxyefavirenz might undergo 14-hydroxylation in vivo. In conclusion, efavirenz metabolism is complex, involving unique and novel secondary metabolism. Although efavirenz 8-hydroxylation by CYP2B6 remains the major clearance mechanism of efavirenz, CYP2A6-mediated 7-hydroxylation (and to some extent 8-hydroxylation) may also contribute. Efavirenz may be a valuable dual phenotyping tool to study CYP2B6 and CYP2A6, and this should be further tested in vivo.
We performed comprehensive kinetic, inhibition, and correlation analyses in human liver microsomes and experiments in expressed human cytochromes P450 (P450s) to identify primary and secondary ...metabolic routes of tamoxifen (TAM) and the P450s catalyzing these reactions at therapeutically relevant concentrations. N-Desmethyl-TAM formation catalyzed by CYP3A4/5 was quantitatively the major primary metabolite of TAM; 4-hydroxy-TAM formation catalyzed by CYP2D6 (and other P450s) represents a minor route. Other minor primary metabolites include alpha -, 3-, and 4'-hydroxyTAM and one unidentified metabolite (M-I) and were primarily catalyzed by CYP3A4, CYP3A5, CYP2B6/2C19, and CYP3A4, respectively. TAM secondary metabolism was examined using N-desmethyl- and 4-hydroxy-TAM as intermediate substrates. N-Desmethyl-TAM was predominantly biotransformed to alpha-hydroxy N-desmethyl-, N-didesmethyl-, and 4-hydroxy N-desmethyl-TAM (endoxifen), whereas 4-hydroxy-TAM was converted to 3,4-dihydroxyTAM and endoxifen. Except for the biotransformation of N-desmethyl-TAM to endoxifen, which was exclusively catalyzed by CYP2D6, all other routes of N-desmethyl- and 4-hydroxy-TAM biotransformation were catalyzed predominantly by the CYP3A subfamily. TAM and its primary metabolites undergo extensive oxidation, principally by CYP3A and CYP2D6 to metabolites that exhibit a range of pharmacological effects. Variable activity of these P450s, brought about by genetic polymorphisms and drug interactions, may alter the balance of TAM effects in vivo.
The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active ...forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen.
We studied 282 patients with hormone receptor-positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d.
CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio HR = 9.52; 95% CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with <or= one risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4-hydroxytamoxifen (P = .0000043 and .00052), whereas no significant difference was found among ABCC2 genotype groups.
Our results suggest that polymorphisms in CYP2D6 and ABCC2 are important predictors for the prognosis of patients with breast cancer treated with tamoxifen.
Polymorphisms in tamoxifen metabolizing genes affect the plasma concentration of tamoxifen metabolites, but their effect on clinical outcome is unknown.
We determined cytochrome P450 (CYP)2D6 (*4 and ...*6) and CYP3A5 (*3) genotype from paraffin-embedded tumor samples and buccal cells (living patients) in tamoxifen-treated women enrolled onto a North Central Cancer Treatment Group adjuvant breast cancer trial. The relationship between genotype and disease outcome was determined using the log-rank test and Cox proportional hazards modeling.
Paraffin blocks were obtained from 223 of 256 eligible patients, and buccal cells were obtained from 17 living women. CYP2D6 (*4 and *6) and CYP3A5 (*3) genotypes were determined from 190, 194, and 205 patient samples and in 17 living women. The concordance rate between buccal and tumor genotype was 100%. Women with the CYP2D6 *4/*4 genotype had worse relapse-free time (RF-time; P = .023) and disease-free survival (DFS; P = .012), but not overall survival (P = .169) and did not experience moderate to severe hot flashes relative to women heterozygous or homozygous for the wild-type allele. In the multivariate analysis, women with the CYP2D6 *4/*4 genotype still tended to have worse RFS (hazard ratio HR, 1.85; P = .176) and DFS (HR, 1.86; P = .089). The CYP3A5*3 variant was not associated with any of these clinical outcomes.
In tamoxifen-treated patients, women with the CYP2D6 *4/*4 genotype tend to have a higher risk of disease relapse and a lower incidence of hot flashes, which is consistent with our previous observation that CYP2D6 is responsible for the metabolic activation of tamoxifen to endoxifen.
CYP2B6*6 and CYP2B6*18 are the most clinically important variants causing reduced CYP2B6 protein expression and activity. However, these variants do not account for all variability in CYP2B6 ...activity. Emerging evidence has shown that genetic variants in the 3′UTR may explain variable drug response by altering microRNA regulation. Five 3′UTR variants were associated with significantly altered efavirenz AUC0‐48 (8‐OH‐EFV/EFV) ratios in healthy human volunteers. The rs70950385 (AG>CA) variant, predicted to create a microRNA binding site for miR‐1275, was associated with a 33% decreased CYP2B6 activity among normal metabolizers (AG/AG vs. CA/CA (P < 0.05)). In vitro luciferase assays were used to confirm that the CA on the variant allele created a microRNA binding site causing an 11.3% decrease in activity compared to the AG allele when treated with miR‐1275 (P = 0.0035). Our results show that a 3′UTR variant contributes to variability in CYP2B6 activity.
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