Influence of the folate pathway and transporter polymorphisms on methotrexate treatment outcome in osteosarcoma

Goričar, Katja; Kovač, Viljem; Jazbec, Janez; Zakotnik, Branko; Lamovec, Janez; Dolžan, Vita

doi:10.1097/fpc.0000000000000083

Cited by 31 publications

(47 citation statements)

References 28 publications

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“…The rs11045879 and rs4149081 polymorphisms have been associated with methotrexate plasma concentration and toxicity. [19][20][21][22] Neither rs113681054 nor rs4149056 affected efficacy and safety endpoints of patients treated with ticagrelor in the PLATO trial. 7) In agreement with the findings from PLATO trial, we also observed that these two variants exhibited no influence on ticagrelor PD parameters in our study.…”

Section: Discussionmentioning

confidence: 99%

No Effect of SLCO1B1 and CYP3A4/5 Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Male Subjects

et al. 2017

Biological & Pharmaceutical Bulletin

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Ticagrelor is a direct-acting P2Y12 receptor antagonist. It is rapidly absorbed and partly metabolized to the active metabolite AR-C124910XX by CYP3A4 and CYP3A5. Three genetic loci (SLCO1B1, CYP3A4, and UGT2B7) were reported to affect ticagrelor pharmacokinetics. This study aimed to investigate the possible effects of SLCO1B1 and CYP3A4/5 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese male volunteers. Eighteen healthy male volunteers who participated in pharmacogenetics study of ticagrelor were genotyped for SLCO1B1 rs113681054, SLCO1B1*5 (rs4149056), CYP3A4*1G (rs2242480), and CYP3A5*3 (rs776746). All subjects received a single 180 mg loading dose of ticagrelor and then series blood samples were collected from 0 to 48 h. Plasma concentrations of ticagrelor and AR-C124910XX were determined by the high performance liquid chromatography-tandem mass spectrometry method. Inhibition in platelet aggregation (IPA) was assessed and the area under the time-effect curve (AUEC) for the IPA was calculated as pharmacodynamic parameters. No significant difference in ticagrelor pharmacokinetics among genotypes of the two genes was observed. The AUEC did not differ significantly among genotypes of candidate single nucleotide polymorphisms (SNPs). Our data suggest that common genetic variants in SLCO1B1 and CYP3A4/5 may have no effect on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese volunteers. Key words ticagrelor; pharmacokinetics; pharmacodynamics; SLCO1B1; CYP450Ticagrelor is the first reversible P2Y12 receptor inhibitor that provides faster onset/offset of pharmacological action and more consistent platelet inhibition compared to clopidogrel. It is recommended for combination therapy with aspirin in patients presenting with acute coronary syndrome (ACS) and undergoing percutaneous coronary intervention (PCI). In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor was observed to reduce the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke, but showed similar rates of major bleeding compared with clopidogrel. 1)As compared with clopidogrel, ticagrelor does not require metabolic activation to exert its antiplatelet effects. The major active metabolite of ticagrelor, AR-C124910XX (ARC), is formed via the hepatic CYP enzyme, CYP3A4 and CYP3A5.2) ARC is present in the blood at about 30-40% of the concentration of ticagrelor with a similar antiplatelet activity. Like other antiplatelet drugs, ticagrelor also shows interindividual variation in platelet inhibitory response in patients with ACS.3)At present, no genetic determinants for the ticagrelor pharmacodynamics (PD) are known, [4][5][6] although several genetic loci (SLCO1B1, UGT2B7, and CYP3A4) were reported to affect the pharmacokinetics (PK) of ticagrelor in Caucasian patients with ACS. 7) However, single nucleotide polymorphisms (SNPs) in the PK related genes showed no effects on efficacy or safety of ticagrelor. 7) Our previous studies r...

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Section: Discussionmentioning

confidence: 99%

No Effect of SLCO1B1 and CYP3A4/5 Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Male Subjects

et al. 2017

Biological & Pharmaceutical Bulletin

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“…Therefore, the overall contribution of SLCOB1B variants to explaining interindividual variability in MTX pharmacokinetics is < 15%, and the major genetic contributors are unknown yet. Recently, Goricar et al found that 'low-clearance' SLCOB1B variants were associated with increased MTX disposition (serum levels at 24 h after HDMTX and AUC) and better outcomes in patients with HGOS [6]. As this investigation encompassed only 44 patients, confirmation of the findings in large cohorts are necessary before any firm conclusions can be drawn.…”

mentioning

confidence: 86%

Can pharmacogenomics help to improve therapy in patients with high-grade osteosarcoma?

Kager

Diakos

Bielack

2015

Expert Opinion on Drug Metabolism & Toxicology

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“…Because of its poor diagnosis, a 5-year survival rate of osteosarcoma patients after amputation is only 40 % [4]. Following the development of medical technology, a 5-year survival rate improved significantly and it got up from 50-70 % [5]. However, the mortality ratio of osteosarcoma remains very high because of tumors' rapid migration and proliferation [6,7].…”

Section: Introductionmentioning

confidence: 99%

Genetic variations in the PRKCG gene and osteosarcoma risk in a Chinese population: a case-control study

Zhu

Lian

et al. 2015

Tumor Biol.

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Osteosarcoma is a common malignant tumor, which exists widely in the bone of children and adolescents. Protein kinase C gamma (PRKCG) gene, which encodes γPKC, plays important roles in tumor promotion, cell proliferation, differentiation, and migration. The objective of the present study was to investigate the relationship between PRKCG polymorphisms and the risk of osteosarcoma. Five tag single nucleotide polymorphisms (SNPs) of PRKCG were retrieved from the HapMap database and genotyped by the method of SNapShot in a hospital-based study containing 388 patients and 388 healthy individuals. Odds ratios (ORs) and their 95 % confidence intervals (CIs) were used to evaluate the association SPSS 20.0 statistical software package was used to analyze statistical data. Our results suggested that the T/C variant of rs454006 located in the intron 3 region of PRKCG gene was significantly associated with an increased risk of osteosarcoma (CC vs. TT, OR = 1.91; 95 % CI 1.29-2.85; P = 0.001; CC vs. TT+TC, OR = 2.14, 95 % CI = 1.48-3.09, P = 0.001; C vs. T, OR = 1.32, 95 % CI = 1.08-1.62, P = 0.008). Similarly, the rs3745406 T/C variant can also elevate the risk of osteosarcoma in the dominant model (OR = 1.45, 95 % CI = 1.08-1.96, P = 0.014), homozygous model (OR = 1.68, 95 % CI = 1.10-2.59, P = 0.002), and allelic model (OR = 1.31, 95 % CI = 1.07-1.61, P = 0.009). However, there were no significant differences in genotypes and allele frequencies of rs2547362 (T>C), rs8103851 (C>G), and rs2242245 (T>C) SNPs between osteosarcoma patients and healthy controls. The results showed that carrier of rs454006*C allele and rs3745406*C might elevate the risk of osteosarcoma. Further studies are needed to validate the coalition between PRKCG gene polymorphisms and risk of osteosarcoma relying on a larger population that included the participants in different ethnicity and hospital.

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Influence of the folate pathway and transporter polymorphisms on methotrexate treatment outcome in osteosarcoma

Abstract: We have shown that SLCO1B1 polymorphisms influence methotrexate disposition and survival in methotrexate-treated osteosarcoma patients and therefore might serve as pharmacogenetic markers of treatment outcome.

Cited by 31 publications

References 28 publications

No Effect of <i>SLCO1B1</i> and <i>CYP3A4/5</i> Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Male Subjects

No Effect of <i>SLCO1B1</i> and <i>CYP3A4/5</i> Polymorphisms on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Male Subjects

Can pharmacogenomics help to improve therapy in patients with high-grade osteosarcoma?

Genetic variations in the PRKCG gene and osteosarcoma risk in a Chinese population: a case-control study

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