ABCB1 Single Nucleotide Polymorphisms Research Articles

Pharmacogenomics of Novel Direct Oral Anticoagulants: Newly Identified Genes and Genetic Variants.

Direct oral anticoagulants (DOAC) have shown an upward prescribing trend in recent years due to favorable pharmacokinetics and pharmacodynamics without requirement for routine coagulation monitoring. However, recent studies have documented inter-individual variability in plasma drug levels of DOACs. Pharmacogenomics of DOACs is a relatively new area of research. There is a need to understand the role of pharmacogenomics in the interpatient variability of the four most commonly prescribed DOACs, namely dabigatran, rivaroxaban, apixaban, and edoxaban. We performed an extensive search of recently published research articles including clinical trials and in-vitro studies in PubMed, particularly those focusing on genetic loci, single nucleotide polymorphisms (SNPs), and DNA polymorphisms, and their effect on inter-individual variation of DOACs. Additionally, we also focused on commonly associated drug-drug interactions of DOACs. CES1 and ABCB1 SNPs are the most common documented genetic variants that contribute to alteration in peak and trough levels of dabigatran with demonstrated clinical impact. ABCB1 SNPs are implicated in alteration of plasma drug levels of rivaroxaban and apixaban. Studies conducted with factor Xa, ABCB1, SLCOB1, CYP2C9, and VKORC1 genetic variants did not reveal any significant association with plasma drug levels of edoxaban. Pharmacokinetic drug-drug interactions of dabigatran are mainly mediated by p-glycoprotein. Strong inhibitors and inducers of CYP3A4 and p-glycoprotein should be avoided in patients treated with rivaroxaban, apixaban, and edoxaban. We conclude that some of the inter-individual variability of DOACs can be attributed to alteration of genetic variants of gene loci and drug-drug interactions. Future research should be focused on exploring new genetic variants, their effect, and molecular mechanisms that contribute to alteration of plasma levels of DOACs.

Selected ABCB1 Single Nucleotide Polymorphisms and Its Haplotype – Connection with Depression Development and Treatment Efficacy

Selected ABCB1 Single Nucleotide Polymorphisms and Its Haplotype – Connection with Depression Development and Treatment Efficacy

Influence of CYP3A and ABCB1 Single Nucleotide Polymorphisms on the Pharmacokinetics/Pharmacodynamics of Tacrolimus in Pediatric Patients.

Single Nucleotide Polymorphisms (SNPs) are very common variants of many genes and are also promising markers associated with drug reactions in pharmacogenomics research. In pediatric organ transplantation, tacrolimus is a major immunosuppressive agent used to prevent organ rejection. The SNP of these genes have been studied extensively in adult population, but there is no systematic review in children. This article focuses on the effects of ABCB1 and CYP3A SNPs on tacrolimus in children who are undergoing organ transplantations. We searched the literature that provided the effect of SNP on metabolism and pharmacokinetics of tacrolimus in pediatric patients in Google, Science Direct and PubMed. Then we accessed the methods used in these studies, the sample size, the model and the conclusions they have obtained. We found that there is no evidence shown that CYP3A4 SNP has an influence on the pharmacokinetic/ pharmacodynamics of tacrolimus in the population of children. Moreover, most studies have failed to find a link between the ABCB1 SNP and the pharmacokinetics of tacrolimus in children. However, although the amount of literature is limited, it does show a link between ABCB1 SNPs and tacrolimus pharmacodynamics. In addition, the literature shows a strong link between CYP3A5 SNP and pharmacokinetics of tacrolimus, but there is no direct evidence that CYP3A5 SNP has the same effect on the pharmacodynamics of tacrolimus. More standardized clinical trials are needed to assess the relationship between CYP3A5 SNP and tacrolimus pharmacodynamics in children, particularly in terms of acute rejection and nephrotoxicity.

Effect of ABCB1 Genotypes on the Pharmacokinetics and Clinical Outcomes of New Oral Anticoagulants: A Systematic Review and Meta-analysis.

New Oral Anticoagulants (NOACs) are effective and widely used to prevent and treat thromboembolic diseases, but the response to NOACs differs according to ABCB1 genotypes. We investigated the effects of ABCB1 genotypes on the pharmacokinetics and clinical outcomes of NOACs. We searched PubMed, Embase, and the Cochrane Library for studies on ABCB1 genotypes published from the inception of these databases until May 23, 2018. The Weighted Mean Difference (WMD) and Odds Ratio (OR) with 95% Confidence Interval (CI) were calculated for continuous and dichotomous data, respectively. Summary results were calculated using a random effects model. Ten studies involving 2609 individuals were included in the systematic review, and three studies involving 535 individuals were included in the meta-analysis. Overall, four ABCB1 single-nucleotide polymorphisms were identified in the review. Carriers of the ABCB1 rs1045642 CC genotype had lower maximum plasma concentration (Cmax) than those of TT (WMD = -16.99 ng/mL; 95% CI = -33.39 to -0.59; P = 0.04), and carriers of the rs2032582 GG genotype showed lower Cmax than those of the A/T allele (WMD = -19.21 ng/mL; 95% CI = -36.62 to -1.80; P = 0.03). Carriers of the rs1045642 CC genotype showed lower area under the curve from time 0 to infinity (AUC0-∞) than those of the T allele (WMD = -78.58 ng·h/mL; 95% CI = -151.14 to -6.01; P = 0.03). ABCB1 rs4148738 genotypes did not affect the risks of ischemic stroke or systemic embolism (OR = 0.88), ischemic events (OR = 0.98), bleeding (OR = 0.94), major bleeding (OR = 1.14), or minor bleeding (OR = 0.94) in patients treated with dabigatran. Cmax was lower in carriers of ABCB1 rs1045642 CC than in those of TT and in carriers of rs2032582 GG than in those of the A/T allele, and AUC0-∞ was lower in carriers of rs1045642 CC than in those of TT. Conversely, ABCB1 rs4148738 genotypes did not affect primary clinical endpoints in dabigatran-administered patients. Future studies should analyze the relationships of ABCB1 genotypes with the pharmacokinetics and clinical outcomes of specific NOACs.

The influence of polymorphisms in the drug transporter, ABCB1 on the toxicity of glucocorticoids in Saudi children with acute lymphoblastic leukaemia.

Glucocorticoids play essential roles in the treatment of childhood acute lymphoblastic leukaemia (ALL); however, treatment with these agents can result in severe side-effects. This study, the first of its kind in a Saudi population, investigates associations of ABCB1 gene polymorphisms (pharmacodynamics and pharmacokinetic) with the development of toxicity and side effects (glucose abnormality, liver toxicity and infection) in a small population of Saudi children with ALL. Three single nucleotide polymorphisms (SNPs) of the ABCB1 gene (rs 3213619 T129C, rs 2032582 G2677T and rs1045642 C3435T) were analysed in 70 Saudi children with ALL and 60 control subjects. Participants were treated according to the ALL 2000 study protocol. Toxicities were assessed and associations with genotypes were evaluated according to Common Toxicity Criteria (NCI-CTC). Significant associations were observed among carriers and the mutated genotype C3435T (ABCB1), which had an incidence of infection (p = 0.05). Although no correlations were found between liver toxicity and glucose abnormalities for patients carrying ABCB1 SNPs, risk factors for liver toxicity were elevated by a factor of three for patients carrying the SNP G2677T, OR 3.00 (1.034-8.702). The risk factor of glucose abnormality toxicity for the patients carring T129C were increased three times OR 3.06 (0.486-19.198). In terms of infection incidence, polymorphism C3435T may contribute to potential life-threatening infections during paediatric ALL therapy, through glucocorticoid usage.

Effect of ABCB1 genetic polymorphisms on the transport of rivaroxaban in HEK293 recombinant cell lines

Direct oral anticoagulants (DOAC) are substrates for the ABCB1 transporter (also called P-glycoprotein), an active efflux pump. ABCB1 polymorphisms have been previously reported to influence the pharmacokinetics of several drugs such as immunosuppressants and tyrosine kinase inhibitors. Recently, in vivo studies have suggested that genetic variants might contribute to the inter-individual variability in DOAC plasma concentrations. Therefore, we evaluated the in vitro effect of the most common coding ABCB1 single nucleotide polymorphisms (SNP), 1236 C > T-2677G > T-3435C > T, and the coding ABCB1 1199 G > A SNP on the transport activity towards rivaroxaban. HEK293 cells were transfected to overexpress the ABCB1 wild-type (1236C-2677G-3435C, 1199 G) or variant proteins (1236C-2677G-3435T, 1236T-2677T-3435T or 1199 A). ABCB1 expression decreased the intracellular accumulation of rivaroxaban, when compared to control cells. This confirms the involvement of ABCB1 in the active transport of rivaroxaban. However, the ABCB1 1236 C > T-2677G > T-3435C > T and 1199 G > A SNPs had no significant influence on the intracellular accumulation of rivaroxaban when compared to the wild-type protein. These results suggest that the ABCB1 coding SNPs investigated in the present study are unlikely to contribute to the inter-individual variability in rivaroxaban plasma concentrations.

Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients.

Most lung transplantation immunosuppression regimens include tacrolimus. Single nucleotide polymorphisms (SNPs) in genes important to tacrolimus bioavailability and clearance (ABCB1, CYP3A4, and CYP3A5) are associated with differences in tacrolimus pharmacokinetics. We hypothesized that polymorphisms in these genes would impact immunosuppression-related outcomes. We categorized ABCB1, CYP3A4, and CYP3A5 SNPs for 321 lung allograft recipients. Genotype effects on time to therapeutic tacrolimus level, interactions with antifungal medications, concentration to dose (C0 /D), acute kidney injury, and rejection were assessed using linear models adjusted for subject characteristics and repeat measures. Compared with CYP3A poor metabolizers (PM), time to therapeutic tacrolimus trough was increased by 5.1±1.6days for CYP3A extensive metabolizers (EM, P<0.001). In the post-operative period, CYP3A intermediate metabolizers spent 1.2±0.5days less (P=0.01) and EM spent 2.1±0.5days less (P<0.001) in goal tacrolimus range than CYP3A PM. Azole antifungals interacted with CYP3A genotype in predicting C0 /D (P<0.001). Increased acute kidney injury rates were observed in subjects with high ABCB1 function (OR 3.0, 95% CI 1.1-8.6, P=0.01). Lower rates of acute cellular rejection were observed in subjects with low ABCB1 function (OR 0.36, 95% CI 0.07-0.94, P=0.02). Recipient genotyping may help inform tacrolimus dosing decisions and risk of adverse clinical outcomes.

Genetic Polymorphisms Associated With Constipation and Anticholinergic Symptoms in Patients Receiving Clozapine.

Clozapine impairs gastrointestinal motility owing to its anticholinergic and antiserotonergic properties. This commonly leads to constipation and potentially to more severe complications such as bowel obstruction and ischemia. The aim of this study was to determine whether genetic variations in the genes encoding muscarinic and serotonergic receptors (CHRM2, CHRM3, HTR2, HTR3, HTR4, and HTR7) explain the variations in incidence of constipation and anticholinergic symptoms during clozapine treatment. Genes associated with opiate-induced constipation were also included in this analysis (TPH1, OPRM1, ABCB1, and COMT). Blood samples from 176 clozapine-treated, Finnish, white patients with schizophrenia were genotyped. Constipation and anticholinergic symptoms were rated using the Liverpool University Neuroleptic Side Effect Rating Scale self-report questionnaire. In total, 192 single-nucleotide polymorphisms (SNPs) were detected and grouped to formulate a weighted genetic-risk score (GRS). No significant associations between individual SNPs or GRSs and constipation or laxative use were observed. A GRS of 19 SNPs in CHRM2, CHRM3, HTR3C, HTR7, ABCB1, OPRM1, and TPH1 was associated with anticholinergic symptoms in a generalized linear univariate model, with body mass index, clozapine monotherapy, and GRS as explaining variables (permuted P = 0.014). Generalized linear univariate model analysis performed on the opiate-induced constipation-associated SNPs and a single CHRM3 SNP revealed an association between anticholinergic symptoms and a score of 8 SNPs (adjusted P = 0.038, permuted P = 0.002). Two GRSs are able to predict the risk of anticholinergic symptoms in patients receiving clozapine and possibly an increased risk of gastrointestinal hypomotility.

Pharmacogenetic study of the impact of ABCB1 single-nucleotide polymorphisms on lenalidomide treatment outcomes in patients with multiple myeloma: results from a phase IV observational study and subsequent phase II clinical trial

PurposeDespite therapeutic advances, patients with multiple myeloma (MM) continue to experience disease relapse and treatment resistance. The gene ABCB1 encodes the drug transporter P-glycoprotein, which confers resistance through drug extrusion across the cell membrane. Lenalidomide (Len) is excreted mainly via the kidneys, and, given the expression of P-gp in the renal tubuli, single-nucleotide polymorphisms (SNPs) in the ABCB1 gene may influence Len plasma concentrations and, subsequently, the outcome of treatment. We, therefore, investigated the influence of ABCB1 genetic variants on Len treatment outcomes and adverse events (AEs).MethodsNinety patients with relapsed or refractory MM, who received the second-line Len plus dexamethasone in the Rev II trial, were genotyped for the ABCB1 SNPs 1199G>A (Ser400Asn, rs2229109), 1236C>T (silent, rs1128503), 2677G>T/A (Ala893Ser, rs2032582), and 3435C>T (silent, rs1045642) using pyrosequencing, and correlations to response parameters, outcomes, and AEs were investigated.ResultsNo significant associations were found between genotype and either best response rates or hematological AEs, and 1236C>T, 2677G>T or 3435C>T genotypes had no impact on survival. There was a trend towards increased time to progression (TTP) in patients carrying the 1199A variant, and a significant difference in TTP between genotypes in patients with standard-risk cytogenetics.ConclusionsOur findings show a limited influence of ABCB1 genotype on lenalidomide treatment efficacy and safety. The results suggest that 1199G>A may be a marker of TTP following Len treatment in standard-risk patients; however, larger studies are needed to validate and clarify the relationship.

907P - Impact of CYP3A4*22 on pazopanib pharmacokinetics in cancer patients

Background: Pazopanib is characterized by a large interpatient variability in systemic drug exposure. As pazopanib trough levels (>20.5 mg/L) are correlated with clinical outcome (Suttle et al, BJC 2014) in metastatic renal cell carcinoma (mRCC) patients, it is vital to identify factors that influence pazopanib pharmacokinetics (PK). The objective of the current analysis was to evaluate if single nucleotide polymorphisms (SNPs) in the metabolic pathway of pazopanib (i.e. CYP3A4, ABCB1 and ABCG2) affect systemic pazopanib concentrations. Methods: We analyzed 97 patients who participated in 3 pazopanib PK studies. Starting point of the current analysis was a population PK model for pazopanib (Yu et al, Clin Pharmacokinet 2017). Four SNPs located on 3 genes, that were associated with decrease of function were analyzed using real time PCR: CYP3A4 15389 C>T (*22), ABCB1 3435 C>T, and the ABCG2 SNPs 421 C>A, and 34G>A. The influence of these SNPs on pazopanib bioavailability and clearance (CL) was explored with NONMEM. Statistical significance was determined with the likelihood ratio test using the objective function value (OFV). Trough concentrations (Ctrough) at 6 weeks after start with doses of 400 to 800 mg once daily (OD), were simulated. A threshold Ctrough of 20.5 mg/L was used as reference. Results: From 3 patients, insufficient DNA was isolated to run a PCR analysis. All SNPs were in Hardy-Weinberg equilibrium. Eleven patients (12%) had a variant allele at CYP3A4*22, all of whom were heterozygous. Incorporation of CYP3A4*22 in the NONMEM model resulted in a 35% lower CL for the variant carriers (0.18 L/h vs 0.27 L/h; ΔOFV = -7.8; P < 0.01). Simulated median Ctrough of patients with CYP3A4*22 with 400 mg OD, 600 mg OD or 800 mg OD were 16 mg/L, 25 mg/L and 33 mg/L, respectively. Simulated Ctrough for the population excluding the CYP3A4*22 heterozygotes after 800 mg OD was 21 mg/L. No effect of the ABCB1 or ABCG2 SNPs on systemic concentrations were found. Conclusions: Our analysis shows that CYP3A4*22 carriers have a clinically relevant lower pazopanib CL. Prospective analysis should point out whether CYP3A4*22 carriers are at risk for more toxicity and require a lower pazopanib starting dose. Legal entity responsible for the study: Erasmus MC, Rotterdam, The Netherlands Funding: None Disclosure: All authors have declared no conflicts of interest.

Transporter genes ABCG2 rs2231142 and ABCB1 rs1128503 polymorphisms and atorvastatin response in Chilean subjects.

Statins are first-line therapy for reducing high cholesterol levels. However, response to these drugs shows high interindividual variability. We aimed to investigate the influence of two single nucleotide polymorphisms (SNP) (ABCB1 rs1128503 and ABCG2 rs2231142) in the ABC transporter genes on response to short-term low-dose atorvastatin in Chilean hypercholesterolaemic patients. We studied 127 Chilean hypercholesterolaemic patients treated with 10mg/d atorvastatin for 4weeks. The lipid profile was determined before and after drug administration. Genotyping of the rs1128503 and rs2231142 variants was performed using TaqMan® Drug Metabolism Genotyping Assays. Genotype distribution for all polymorphisms investigated was consistent with the Hardy-Weinberg equilibrium. Atorvastatin reduced TC, LDL-C and TG concentrations (P<.05), whereas HDL-C levels were found to be increased (P<.05). Minor allele frequencies for rs1128503 and rs2231142 variants were 0.453 and 0.075, respectively. In this study, patients prescribed with short-term low-dose atorvastatin and carrying ABCB1 (rs1128503) or ABCG2 (rs2231142) SNPs did not show differences in LDL-C response (P>.05). The ABCB1 SNP was not associated with response to atorvastatin in Chilean subjects. The few ABCG2 421A homozygotes did not allow meaningful inferences to be made for this polymorphism.

ABCB1 3435C>T and 2677G>T/A polymorphisms in Polish and Bosnian patients with Crohn's disease - A preliminary report.

The role of ABCB1 single nucleotide polymorphisms (SNPs) in the development of Crohn's disease (CD) remains unclear. Due to inconsistent results of several European population-based studies and limited information on populations from Poland and Bosnia and Herzegovina (B&H), we conducted a preliminary association study of two main ABCB1 SNPs and CD. ABCB1 3435C>T and 2677G>T/A SNPs were analyzed in Polish and Bosnian patients with CD (n = 85 and n = 30, respectively) and controls (n = 82 and n = 30, respectively) using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for 3435C>T and allele-specific PCR for 2677G>A/T SNP. A deviation from Hardy-Weinberg equilibrium was found for both SNPs in Polish patients with CD, and for 2677G>A/T in Polish control group. The allele and genotype frequencies of the two ABCB1 SNPs were not significantly different between the CD patients and controls in both populations (p > 0.05). Similarly, the genotype distribution of 3435C>T and 2677G>T/A SNPs was not significantly different between Polish and Bosnian patients with CD (p > 0.05). At least one mutated ABCB1 allele was carried by 97.7% of Polish and 90.0% of Bosnian patients with CD. No association was found between the ABCB1 SNPs and CD in the two populations. In conclusion, the two ABCB1 SNPs may not contribute to CD susceptibility in the populations of Poland and B&H. Further studies with larger samples in both populations are warranted.

Abstract 5030: The impact of ABCB1 single nucleotide polymorphisms on the outcome in lenalidomide treated multiple myeloma patients

Abstract Introduction: Multiple myeloma (MM) is an incurable plasma cell malignancy with high mortality rate. Treatment outcomes have improved since the introduction of new drugs such as the IMiD lenalidomide, but relapse rates and resistance is still a problem. The gene ABCB1 encodes the drug transporter p-glycoprotein (p-gp) which confers resistance through extrusion of drugs over the cell membrane. Lenalidomide is subject to limited metabolism and excreted mainly via the kidneys. In vitro studies have shown lenalidomide to be an ABCB1 substrate, and single nucleotide polymorphisms (SNPs) affecting gene expression, transporter function and/or activity may affect drug distribution and the subsequent outcome and risk of adverse events. However, in vivo studies of the effect of ABCB1 on lenalidomide pharmacokinetics are contradictory. Our aim was to investigate the influence of ABCB1 SNPs on lenalidomide treatment outcome and adverse events (AE). Materials &amp; Methods: In the observational part of two connected studies, 133 Lenalidomide naïve patients at 1st relapse/refractory MM were treated with lenalidomide and dexamethasone for up to 9 cycles of 4 weeks. In the prospective 2nd part, 62 patients that had achieved at least partial response according to IMWG-criteria followed by at least two additional treatment cycles were randomized to either lenalidomide/dexamethasone or lenalidomide as a single drug. 90 patients (of which 47 was further randomized to the 2nd part) had samples available for genotyping of the ABCB1 SNPs 1199G&amp;gt;A (Ser400Asn, rs2229109), 1236C&amp;gt;T (rs1128503), 2677G&amp;gt;T/A (Ala893Ser, rs2032582) and 3435C&amp;gt;T (rs1045642) using Pyrosequencing. Correlations to overall survival, time to progression (TTP), response parameters and AE were investigated, and a p-value of 0.05 was considered significant. Results: No significant correlations to hematological AE or response rates were found, and no impact on survival for 1236C&amp;gt;T, 2677G&amp;gt;T/A or 3435C&amp;gt;T, neither in the whole population nor in patients randomized to the 2nd part. The results were similar also when risk (according to FISH) was considered. There was a trend towards improved TTP for patients carrying the 1199A variant; mean TTP 3.2 years (95%CI 2.3-4.1) vs 2.2 years (95%CI 1.8-2.6) for G/A and G/G, respectively (p=0.076). This trend was confirmed in the multivariable cox regression analysis; HR=0.280 (95%CI 0.74-1.054), p=0.06. The difference in TTP was significant in the non-high risk subgroup; mean TTP 4.3 years (95%CI 3.7-4.9) vs 2.3 years (95%CI 1.8-2.8), p=0.034, for G/A and G/G, respectively. Conclusion: No evidence was found for a large impact of 1236C&amp;gt;T, 2677G&amp;gt;T/A or 3435C&amp;gt;T on lenalidomide treatment outcome or risk of hematological AE. 1199G&amp;gt;A may be a potential marker of TTP in non-high risk MM but further studies in a larger cohort is needed to clarify the relationship and whether this is due to altered drug transport or efflux independent mechanisms. Citation Format: Ingrid Jakobsen Falk, Johan Lund, Henrik Gréen, Astrid Gruber, Evren Alici, Birgitta Lauri, Cecilie Blimark, Ulf-Henrik Mellqvist, Agneta Swedin, Karin Forsberg, Conny Carlsson, Mats Hardling, Lucia Ahlberg, Hareth Nahi, Kourosh Lotfi. The impact of ABCB1 single nucleotide polymorphisms on the outcome in lenalidomide treated multiple myeloma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5030. doi:10.1158/1538-7445.AM2017-5030

ABCB1 genetic variants in leukemias: current insights into treatment outcomes.

Despite improvements in treatment of different types of leukemia, not all patients respond optimally for a particular treatment. Some treatments will work better for some, while being harmful or ineffective for others. This is due to genetic variation in the form of single-nucleotide polymorphisms (SNPs) that affect gene expression or function and cause inherited interindividual differences in the metabolism and disposition of drugs. Drug transporters are one of the determinants governing the pharmacokinetic profile of chemotherapeutic drugs. The ABCB1 transporter gene transports a wide range of drugs, including drugs used in leukemia treatment. Polymorphisms in the ABCB1 gene do affect intrinsic resistance and pharmacokinetics of several drugs used in leukemia treatment protocols and thereby affect the efficacy of treatment and event-free survival. This review focuses on the impact of three commonly occurring SNPs (1236C>T, 2677G>T/A, and 3435C>T) of ABCB1 on treatment response of various types of leukemia. From the literature available, some of the genotypes and haplotypes of these SNPs have been found to be potential determinants of interindividual variability in drug disposition and pharmacologic response in different types of leukemia. However, due to inconsistencies in the results observed across the studies, additional studies, considering novel genomic methodologies, comprehensive definition of clinical phenotypes, adequate sample size, and uniformity in all the confounding factors, are warranted.

Paclitaxel-induced sensory peripheral neuropathy is associated with an ABCB1 single nucleotide polymorphism and older age in Japanese.

Whether age and inter-individual variability of pharmacogenetics are risk factors for paclitaxel-induced peripheral neuropathy (PIPN) is inconclusive. This study was conducted to evaluate the influence of previously investigated single nucleotide polymorphisms (SNPs) and age, using genotype data from a prospective study of paclitaxel-related toxicity in Japanese patients with breast cancer. Peripheral blood mononuclear cells from 127 Japanese women with breast cancer who received weekly adjuvant paclitaxel were used to genotypes SLCO1B3 T334G (rs4149117), CYP2C8 A1196G (rs10509681), ABCB1 C1236T (rs1128503), ABCB1 G2677T/A (rs2032582), and ABCB1 C3435T (rs1045642). Genotypic and clinical factors were investigated for associations with PIPN. Of the five SNPs evaluated, no SNPs were significantly associated with grade 2 or higher PIPN. However, ABCB1 1236 TT showed a trend to associate with grade 2 or higher PIPN compared to ABCB1 CT/CC (odds ratio 2.1, 95% CI 0.991-4.548, p=0.051). In subgroup analysis, patients ≥60years old with an ABCB1 1236 TT had a higher incidence of ≥grade 2 PIPN compared to patients with CT or CC genotype (p=0.027). On multivariable analysis, age ≥60years and the ABCB1 1236 TT showed a significant association with ≥grade 2 PIPN (p=0.005 and p=0.034, respectively). ABCB1 1236 TT genotype and older age might be a predictor of PIPN, which diminishes quality of life of cancer survivors.

ABCB1 and SLCO1B3 Gene Polymorphisms and Their Impact on Digoxin Pharmacokinetics in Atrial Fibrillation Patients among the Tunisian Population

Background: Digoxin is a substrate of P-glycoprotein (P-gp) and organic anion transporting polypeptide transporters that are encoded by ABCB1 and SLCO1B3 genes. Genetic polymorphisms in both genes may explain inter-individual variability of serum digoxin concentration (SDC). This study evaluates the possible effect of the most common ABCB1 and SLCO1B3 polymorphisms on SDC after a single oral dose of digoxin in Tunisian atrial fibrillation (AF) patients. Methods:ABCB1 and SLCO1B3 genotypes were analyzed in 102 patients with AF who received digoxin (0.5 mg) without (group I, n = 58) or with the co-administration of P-gp inhibitors (group II, n = 44). SDCs were determined at 6 h following the oral dose. Results: SDCs levels were significantly higher in patients who were co-administered P-gp inhibitors. No influence was noted in ABCB1 and SLCO1B3 polymorphisms on SDC in group I patients. However, SDCs values were significantly different among ABCB1 single nucleotide polymorphisms (SNPs) genotypes of 2677G>T/A (TT, GG>GT, p < 0.05) and 3435C>T (TT, CC>CT, p < 0.05) only in group II with no effect of 1236C>T and SLCO1B3 SNPs. Conclusion: Results suggest that P-gp inhibitors and ABCB1 gene polymorphisms may affect digoxin pharmacokinetics.

A Prediction Algorithm for Drug Response in Patients with Mesial Temporal Lobe Epilepsy Based on Clinical and Genetic Information.

Mesial temporal lobe epilepsy is the most common form of adult epilepsy in surgical series. Currently, the only characteristic used to predict poor response to clinical treatment in this syndrome is the presence of hippocampal sclerosis. Single nucleotide polymorphisms (SNPs) located in genes encoding drug transporter and metabolism proteins could influence response to therapy. Therefore, we aimed to evaluate whether combining information from clinical variables as well as SNPs in candidate genes could improve the accuracy of predicting response to drug therapy in patients with mesial temporal lobe epilepsy. For this, we divided 237 patients into two groups: 75 responsive and 162 refractory to antiepileptic drug therapy. We genotyped 119 SNPs in ABCB1, ABCC2, CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 genes. We used 98 additional SNPs to evaluate population stratification. We assessed a first scenario using only clinical variables and a second one including SNP information. The random forests algorithm combined with leave-one-out cross-validation was used to identify the best predictive model in each scenario and compared their accuracies using the area under the curve statistic. Additionally, we built a variable importance plot to present the set of most relevant predictors on the best model. The selected best model included the presence of hippocampal sclerosis and 56 SNPs. Furthermore, including SNPs in the model improved accuracy from 0.4568 to 0.8177. Our findings suggest that adding genetic information provided by SNPs, located on drug transport and metabolism genes, can improve the accuracy for predicting which patients with mesial temporal lobe epilepsy are likely to be refractory to drug treatment, making it possible to identify patients who may benefit from epilepsy surgery sooner.

Polymorphisms in CYP1A1 and CYP3A5 Genes Contribute to the Variability in Granisetron Clearance and Exposure in Pregnant Women with Nausea and Vomiting.

Nausea and vomiting affect up to 90% of pregnant women. Granisetron is a potent and highly selective serotonin receptor antagonist and is an effective antiemetic. Findings from a prior study in pregnant women demonstrated a large interindividual variability in granisetron exposure. Granisetron is primarily metabolized by the cytochrome P450 (CYP) enzymes CYP1A1 and CYP3A and is likely a substrate of the ABCB1 transporter. Single-nucleotide polymorphisms (SNPs) in CYP3A, CYP1A1, and ABCB1 can alter drug metabolism. This study evaluated the influence of polymorphisms in CYP3A4, CYP3A5, CYP1A1, and ABCB1 on the pharmacokinetic properties of granisetron in pregnant women. The study enrolled 16 pregnant women (gestational age of 12-19 wks). All patients had nausea and vomiting and were treated with granisetron 1 mg. Granisetron plasma concentrations were determined using liquid chromatography tandem-mass spectrometry. The patients' genotype was determined using TaqMan SNP Genotyping Assays. The Hardy-Weinberg equilibrium was assessed by comparing observed and expected genotype frequencies, using the exact test. Intravenous granisetron clearance was used as the dependent variable for analysis of associations. Of 16 patients, 25% were homozygous for the allele variant CYP3A5*3 and had a significantly lower granisetron clearance and increased area under the plasma concentration-versus-time curve (AUC) compared with nonhomozygous patients. Approximately one-third of patients (n=5) were carriers for the allele variant CYP1A1*2A and had a significantly higher granisetron clearance and decreased AUC. We did not find significant differences in the AUC or clearance for any SNPs in CYP3A4 and ABCB1 genes. Polymorphisms in CYP3A5 and CYP1A1 account for some of the variability in systemic clearance and exposure of granisetron in pregnant women.

Polymorphisms in ABCB1 and CYP19A1 genes affect anastrozole plasma concentrations and clinical outcomes in postmenopausal breast cancer patients.

Anastrozole, an aromatase inhibitor widely used in breast cancer, has recently been indicated to be a P-glycoprotein (ABCB1) substrate. We have aimed to determine whether ABCB1 single-nucleotide polymorphisms (SNPs) can affect anastrozole plasma concentrations in these patients. In addition, we assessed the impact of SNPs in CYP19A1 and TCL1A on the development of arthralgia and cancer recurrence in our series. This study included 110 postmenopausal women with hormone receptor-positive breast cancer. Anastrozole plasma levels were determined by a liquid chromatography-electrospray ionization-quadrupole-time-of-flight mass spectrometry system. Patients were genotyped for SNPs in the ABCB1, TCL1A and CYP19A1 genes to search for associations with pharmacokinetic and pharmacodynamics parameters using logistic regression models. Anastrozole concentrations showed an almost nine-fold interindividual variability (mean 26.95±11.91ngml-1 ). The ABCB1 2677-TT genotype was associated with higher plasma levels (32.22±12.82 vs. 25.86±11.56ngml-1 for GG/GT subjects; 95% confidence interval: -12.3 to -0.40), whilst the 3435-TT genotype showed a protective effect on the risk of arthralgia (odds ratio =0.32 [0.11-0.89]; P=0.029). The CYP19A1 rs1008805 GG genotype was strongly and inversely associated with arthralgia (odds ratio=0.24 [0.09-0.65], P=0.004); however, SNPs near the TCL1A gene were not linked to this adverse effect. None of the patients who had cancer recurrence harboured the CYP19A1 rs727479 AA genotype, which, in contrast, was present in 38% of patients who did not relapse (P for trend=0.031). Our findings indicate that variability in anastrozole plasma levels may be attributable to the status of the ABCB1 gene locus. Furthermore, genetic variants in CYP19A1 were associated with arthralgia and cancer recurrence in our patients.

Pharmacogenetic analysis of high-dose methotrexate treatment in children with osteosarcoma.

Inter-individual differences in toxic symptoms and pharmacokinetics of high-dose methotrexate (MTX) treatment may be caused by genetic variants in the MTX pathway. Correlations between polymorphisms and pharmacokinetic parameters and the occurrence of hepato- and myelotoxicity were studied. Single nucleotide polymorphisms (SNPs) of the ABCB1, ABCC1, ABCC2, ABCC3, ABCC10, ABCG2, GGH, SLC19A1 and NR1I2 genes were analyzed in 59 patients with osteosarcoma. Univariate association analysis and Bayesian network-based Bayesian univariate and multilevel analysis of relevance (BN-BMLA) were applied. Rare alleles of 10 SNPs of ABCB1, ABCC2, ABCC3, ABCG2 and NR1I2 genes showed a correlation with the pharmacokinetic values and univariate association analysis. The risk of toxicity was associated with five SNPs in the ABCC2 and NR1I2 genes. Pharmacokinetic parameters were associated with four SNPs of the ABCB1, ABCC3, NR1I2, and GGH genes, and toxicity was shown to be associated with ABCC1 rs246219 and ABCC2 rs717620 using the univariate and BN-BMLA method. BN-BMLA analysis detected relevant effects on the AUC0-48 in the following SNPs: ABCB1 rs928256, ABCC3 rs4793665, and GGH rs3758149. In both univariate and multivariate analyses the SNPs ABCB1 rs928256, ABCC3 rs4793665, GGH rs3758149, and NR1I2 rs3814058 SNPs were relevant. These SNPs should be considered in future dose individualization during treatment.