Purpose
The study aims to evaluate relationship between polymorphisms associated with a reduced function of two transporter proteins resulting in increased exposure to rosuvastatin — organic anion ...transporter 1B1 (OATP1B1) (
SLCO1B1 c.521T
>
C
) and ATP binding cassette subfamily G member 2 (ABCG2) (
ABCG2 c.421C
>
A
) and occurrence of rosuvastatin related myotoxicity/hepatotoxicity.
Methods
In a case–control study, cases (rosuvastatin treated patients developing myotoxicity or hepatotoxicity) and controls (concurrent rosuvastatin treated patients free of adverse events) were prospectively recruited over a 2 year period in a single tertiary center specialized in treatment of metabolic disorders. Subjects were evaluated for clinical, comorbidity, and comedication characteristics and for genotype predicted metabolizing phenotypes regarding cytochrome P450 enzymes CYP2C9 and CYP2C19. Standard regression analysis and analysis in matched sets of cases and controls (optimal full matching) were undertaken by fitting frequentist and Bayesian models (covariates/matching variables: age, sex, diabetes, liver/renal disease, hypertension, CYP2C9 and C19 phenotype, use of CYP or transporter inhibitors, non evaluated transporter genotype).
Results
A total of 88 cases (81 with myotoxicity, 6 with hepatotoxicity, 1 with both) and 129 controls were recruited. Odds of variant
SLCO1B1 c.521T
>
C
allele were 2.2–2.5 times higher in cases than in controls (OR = 2.45, 95% CI 1.34–4.48; Bayesian OR = 2.59, 95% CrI 1.42–4.90 in regression analysis; OR = 2.20, 1.10–4.42; Bayesian OR = 2.26, 1.28–4.41 in matched analysis). Odds of variant
ABCG2 c.421C
>
A
allele were 2.1–2.3 times higher in cases than in controls (OR = 2.24, 1.04–4.83; Bayesian OR = 2.35, 1.09–4.31 in regression analysis; OR = 2.10, 0.83–5.31; Bayesian OR = 2.17, 1.07–4.35 in matched analysis).
Conclusion
Loss of function polymorphisms in
SLCO1B1
c.
521T
>
C
and
ABCG2
c.
421C
>
A
genes are associated with the presence of rosuvastatin related myotoxicity and/or hepatotoxicity.
Tardive dyskinesia is a neurological disorder characterized by involuntary, repetitive mo-vements of the face, tongue, and limbs, which may result from a long-term use of antip-sychotics.
Uridine diphosphate glucuronosyltransferase-2B7 (UGT2B7), enzyme responsible for the elimination of a number of xenobiotics through glucuronidation, is expressed in the gut, kidneys, intestines, and ...brain. However, data on the frequency of
polymorphisms in the Croatian population are limited. The aim of this study was to assess the frequency of the
(rs7668258) polymorphism in the Croatian population and to compare it with reported frequencies in other populations. This polymorphism is in complete linkage disequilibrium with the
c.
(
, rs7439366) variant, which is important in clinical medicine. The study reports data of 501 participants from University Hospital Centre Zagreb. All data were collected and analysed retrospectively. Genotyping was performed by real-time polymerase chain reaction (PCR) using the TaqMan
Drug Metabolism Genotyping Assay for
(rs7668258). We found that 120 (23.95 %) participants were carriers of the
.-
genotype and 255 (50.9 %) were heterozygous carriers (
.-
), while 126 (25.15 %) were homozygous carriers of the variant allele (
.-
). The frequency of the variant
.-
allele in this study was T=0.506. The frequency of the
.-
allelic variants and genotypes in the Croatian population is similar to other European populations.
Organic anion-transporting polypeptide 1B1 (OATP1B1) and the ATP-binding cassette subfamily G member 2, ABCG2, are important transporters involved in the transport of endogenous substrates and ...xenobiotics, including drugs. Genetic polymorphisms of these transporters have effect on transporter activity. There is significant interethnic variability in the frequency of allele variants.
To determined allele and genotype frequencies of ABCG2 and SLCO1B1 genes in Croatian populations of European descent.
A total of 905 subjects (482 women) were included. Genotyping for ABCG2 c.421C > A (rs2231142) and for SLCO1B1 c.521T > C (rs4149056), was performed by real-time polymerase chain reaction (PCR) using TaqMan
®
DME Genotyping Assays.
For ABCG2 c.421C > A, the frequency of CC, CA and AA genotypes was 81.4%, 17.8% and 0.8% respectively. The frequency of variant ABCG2 421 A allele was 9.7%. For SLCO1B1 c.521T > C, the frequency of TT, TC and CC genotypes was 61.7%, 34.8% and 3.5% respectively. The frequency of variant SLCO1B1 521 C allele was 20.9%.
The frequency of the ABCG2 and SLCO1B1 allelic variants and genotypes in the Croatian population is in accordance with other European populations. Pharmacogenetic analysis can serve to individualise drug therapy and minimise the risk of developing adverse drug reactions.
A recently discovered haplotype-
-determines the ultrarapid metabolism of several CYP2C19 substrates. The platelet inhibitor clopidogrel requires CYP2C19-mediated activation: the risk of ischemic ...events is increased in patients with a poor (PM) or intermediate (IM) CYP2C19 metabolizer phenotype (vs. normal, NM; rapid, RM; or ultrarapid, UM). We investigated whether the
haplotype affected efficacy/bleeding risk in clopidogrel-treated patients. Adults (
= 283) treated with clopidogrel over 3-6 months were classified by CYP2C19 phenotype based on the
genotype, and based on the
cluster genotype, and regarding carriage of the
haplotype, and were balanced on a number of covariates across the levels of phenotypes/haplotype carriage. Overall, 45 (15.9%) patients experienced ischemic events, and 49 (17.3%) experienced bleedings. By either classification, the incidence of ischemic events was similarly numerically higher in PM/IM patients (21.6%, 21.8%, respectively) than in mutually similar NM, RM, and UM patients (13.2-14.8%), whereas the incidence of bleeding events was numerically lower (13.1% vs. 16.6-20.5%). The incidence of ischemic events was similar in
carries and non-carries (14.1% vs. 16.1%), whereas the incidence of bleedings appeared mildly lower in the former (14.9% vs. 20.1%). We observed no signal to suggest a major effect of the
cluster genotype or
haplotype on the clinical efficacy/safety of clopidogrel.
The relevance of the multidrug resistance (ABCB1) and breast cancer resistance (ABCG2) protein transporter polymorphisms for treatment with long-acting intramuscular (LAI) risperidone is largely ...unknown. We explored the relationship between these polymorphisms and cytochrome P450 (CYP) 2D6 genotype-predicted phenotype in their effects on drug disposition and clinical outcomes in adults with schizophrenia. In a 24-week observational study, patients initiated on LAI-risperidone (n=101) were genotyped enzymes (CYP2D6 dupl,*3,*4,*5,*6,*41; CYP3A4*22, CYP3A5*3), transporters (ABCG2 421C>A; ABCB1 1236C>T, 2677G>T/A, 3435C>T) and evaluated for steady-state (weeks 6–8) serum levels of dose-corrected risperidone, 9-OH-risperidone, risperidone+9-OH-risperidone (active moiety), and for response to treatment (PANSS, reduction vs. baseline ≥30% at week 12 and ≥45% at week 24). CYP2D6 normal/ultrarapid metabolizers (NM/UM) (vs. other) had lower risperidone (29%) and active moiety levels (24%) (9-OH-risperidone not affected). The effect on the three analytes was mild (0 to 23% reduction) in ABCG2 wild-type homozygotes and pronounced (44–55% reduction) in ABCG2 variant allele carriers. ABCG2 variant had no effect on disposition in CYP2D6 “other” phenotypes, while the effect was pronounced in CYP2D6 NM/UM subjects (31–37% reduction). ABCB1 polymorphisms had no effect on exposure to risperidone. CYP2D6 NM/UM phenotype tended to lower odds of PANSS response, ABCG2 variant was associated with 4-fold higher odds and ABCB1 (1236C>T, 2677G>T/A, 3435C>T) overall mainly wild-type genotype was associated with around 4--fold lower odds of response. In patients treated with LAI-risperidone, CYP2D6 phenotype effect on systemic exposure is conditional on the ABCG2 421C>A polymorphism. ABCG2 and ABCB1 polymorphisms affect clinical response independently of systemic risperidone disposition.
•CYP2D6 phenotype affects systemic disposition (conditional on ABCG2 polymorphism) and clinical effects of risperidone.•ABCG2 variant results in lower exposure but greater clinical response ro risperidone.•ABCG2 and ABCB1 polymorphisms affect clinical response independently of systemic risperidone disposition.
Aims
Cancer patients with reduced dihydropyrimidine dehydrogenase (DPD) activity are at increased risk of severe fluoropyrimidine (FP)‐related adverse events (AE). Guidelines recommend FP dosing ...adjusted to genotype‐predicted DPD activity based on four DPYD variants (rs3918290, rs55886062, rs67376798 and rs56038477). We evaluated the relationship between three further DPYD polymorphisms: c.496A>G (rs2297595), *6 c.2194G>A (rs1801160) and *9A c.85T>C (rs1801265) and the risk of severe AEs.
Methods
Consecutive FP‐treated adult patients were genotyped for “standard” and tested DPYD variants, and for UGT1A1*28 if irinotecan was included, and were monitored for the occurrence of grade ≥3 (National Cancer Institute Common Terminology Criteria) vs. grade 0–2 AEs. For each of the tested polymorphisms, variant allele carriers were matched to respective wild type controls (optimal full matching combined with exact matching, in respect to: age, sex, type of cancer, type of FP, DPYD activity score, use of irinotecan/UGT1A1, adjuvant therapy, radiotherapy, biological therapy and genotype on the remaining two tested polymorphisms).
Results
Of the 503 included patients (82.3% colorectal cancer), 283 (56.3%) developed grade ≥3 AEs, mostly diarrhoea and neutropenia. Odds of grade ≥3 AEs were higher in c.496A>G variant carriers (n = 127) than in controls (n = 376) OR = 5.20 (95% CI 1.88–14.3), Bayesian OR = 5.24 (95% CrI 3.06–9.12). Odds tended to be higher in c.2194G>A variant carriers (n = 58) than in controls (n = 432) OR = 1.88 (0.95–3.73), Bayesian OR = 1.90 (1.03–3.56). c.85T>C did not appear associated with grade ≥3 AEs (206 variant carriers vs. 284 controls).
Conclusion
DPYD c.496A>G and possibly c.2194G>A variants might need to be considered for inclusion in the DPYD genotyping panel.
Farmakogenomika i farmakovigilancija Božina, Nada
Medicus (Zagreb, Croatia : 1992),
07/2017, Letnik:
26, Številka:
1 Farmakovigilancija
Journal Article
Recenzirano
Odprti dostop
Razvoj nove discipline farmakogenetike/farmakogenomike omogućio je bolje razumijevanje genetičke predispozicije za razvoj neočekivanih reakcija na primijenjeni lijek i posljedično unaprijedio ...individualizaciju farmakoterapije. Postoje genetički određene interindividualne razlike u metaboličkom i transportnom kapacitetu, a time i kinetici lijekova i drugih ksenobiotika. Osim nuspojava lijekova koje su ovisne o dozi važne su nuspojave posredovane imunosnim reakcijama, a povezane su s varijabilnosti u sustavu HLA. Individualna osjetljivost prema toksičnim učincima farmakoterapije, ovisna o biotransformacijskim procesima, povezuje se s genskim polimorfizmima enzima faze I. i II. te transporterima ABC i SLC. Genski polimorfizmi također mogu imati ključnu ulogu u interakcijama lijekova. Povezivanje farmakogenomike s farmakovigilancijom ima važnu ulogu i u praćenju pojavnosti nuspojava poslije stavljanja lijeka na tržište. Regulatorna tijela uvođenjem farmakogenomičkih informacija (informacije o genomskim biljezima) u Sažetku o proizvodu (SPC) nastoje istaknuti ulogu i važnost genomskih varijabilnosti u farmakoterapiji. Također se navodi kojoj kategoriji te farmakogenetičke informacije pripadaju, tj. smatra li se testiranje obvezatnim, ima li ulogu preporuke ili je informativnog karaktera. Radi prikupljanja i implementacije znanja ustanovljeni su i različiti konzorciji među kojima prednjači Clinical Pharmacogenetics Implementation Consortium – CPIC, kao zajednički projekt The Pharmacogenomics Knowledge Base (PharmGKB) i The Pharmacogenomics Research Network koji je okupio eminentne stručnjake iz područja farmakogenetike/farmakogenomike. Glavni je cilj CPIC-a izdavanje recenziranih, ažuriranih, temeljenih na dokazima, slobodno dostupnih uputa i smjernica za primjenu lijeka prema rezultatu farmakogenetičkih analiza. Te će smjernice svakako ubrzati prijenos znanja u kliničku primjenu.
The polymorphic P450 (CYP) enzyme superfamily is the most important system involved in the biotransformation of many endogenous and exogenous substances including drugs, toxins, and carcinogens. ...Genotyping for CYP polymorphisms provides important genetic information that help to understand the effects of xenobiotics on human body. For drug metabolism, the most important polymorphisms are those of the genes coding for CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, which can result in therapeutic failure or severe adverse reactions. Genes coding for CYP1A1, CYP1A2, CYP1B1, and CYP2E1 are among the most responsible for the biotransformation of chemicals, especially for the metabolic activation of pre-carcinogens. There is evidence of association between gene polymorphism and cancer susceptibility. Pathways of carcinogen metabolism are complex, and are mediated by activities of multiple genes, while single genes have a limited impact on cancer risk. Multigenic approach in addition to environmental determinants in large sample studies is crucial for a reliable evaluation of any moderate gene effect. This article brings a review of current knowledge on the relations between the polymorphisms of some CYPs and drug activity/toxicity and cancer risk.
Uloga genskog polimorfizma metaboličkih enzima P450(CYP) kao čimbenika osjetljivosti na učinkovitost i toksičnost lijeka te nastanak karcinoma
Interindividual variability in drug metabolism is an important cause of adverse drug reactions and variability in drug efficiency. Polymorphisms of cytochrome P450 (CYPs) genes have a significant ...effect on drug metabolism and toxicity. This review brings an update about how genetic polymorphisms of CYP2C8 and CYP2C9 enzymes affect the disposition and clinical outcomes of ibuprofen and diclofenac, two of the most common pain relievers. The most common side effects associated with the influence of CYP2C8*3 and CYP2C9*2*3 variants on ibuprofen and diclofenac pharmacokinetics are hepatotoxicity and gastrointestinal bleeding. CYP genotyping may therefore identify patients at increased risk of these adverse reactions, and these patients could have their doses adjusted or start receiving another NSAID that does not share the same metabolic pathways with ibuprofen or diclofenac. However, before genotyping is introduced into regular clinical practice, more research is needed to evaluate the effectiveness of this strategy in improving treatment with ibuprofen and diclofenac.
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