Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The polymorphic gene expression of CYP2C19 causes individual variability in drug metabolism and thereby in pharmacologic and toxicologic responses. We genotyped 286 patients and their donors for the CYP2C19 gene who underwent allogeneic transplantation for various diseases and analyzed their outcome. Patients were classified as: poor metabolizers (PMs; 3.1%), intermediate metabolizers (IMs; 24.5%) and extensive metabolizers (EMs; 72.5%). Patients genotyped as PMs had significant higher hepato- and nephrotoxicities compared to IMs or EMs. Maximum bilirubin and serum creatinine levels measured after transplant were approximately twofold higher than those of EMs or IMs. The increased toxicity resulted in an increased 4-year estimate for transplant-related mortality (TRM) with 50+/-18.6% for PMs compared to 25.1+/-3.7% for EMs (P<0.018) and 22.7 +/-5.6% for IMs (P<0.042), whereas no significant influence for relapse rate, overall survival or incidence of acute graft-versus-host disease grade 2-4 were found between the groups. Multivariate analysis including all potential factors that might influence TRM confirmed that the genotype of CYP2C19 is an independent factor, which influenced TRM significantly. These results suggest that genotyping for CYP450 2C19 can help to identify patients with higher risk for TRM.
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PMID:Cytochrome P450 2C19 loss-of-function polymorphism is associated with an increased treatment-related mortality in patients undergoing allogeneic transplantation. 1768 25

Calcineurin inhibitors are necessary as immunosuppressants during hematopoietic SCT (HSCT) to prevent alloreactivity, but have unfortunate toxicities. So, we investigated the association of gene polymorphisms with the initial calcineurin inhibitor concentration and the subsequent drug dose from day 1 to day 28 among patients who underwent HSCT at a single institution. We analyzed 58 serial cases of Japanese patients receiving GVHD prophylaxis with CsA (21 cases) or tacrolimus (37 cases). We investigated eight single-nucleotide polymorphisms: rs4244285 (CYP2C19), rs15524, rs4646450, rs3800959, rs776746 (CYP3A5), rs1128503, rs2032582 and rs1045642 (MDR1). The CsA concentration was significantly higher when the genotype of CYP3A5 rs15524 was T/T (P=0.044) or rs776746 was G/G (P=0.027). The CYP3A5 rs776746 and rs4646450 genotypes were also associated with tacrolimus concentration (P=0.013 and P=0.0058, respectively). The dosage of tacrolimus was remarkably reduced from day -1 to day 28 when the patient had the CYP3A5 rs4646450 C/C and/or rs776746 G/G genotype (P=0.0010 and P=0.0021, respectively). In this study, we show that genetic variation has a predictable effect on the pharmacological responses to calcineurin inhibitors in HSCT patients.
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PMID:Cytochrome P450 genetic polymorphisms influence the serum concentration of calcineurin inhibitors in allogeneic hematopoietic SCT recipients. 2110 98

Treatment or prophylaxis of invasive fungal infection in recipients of haemopoietic SCT (HSCT) may require management of coexistent malnutrition, organ dysfunction and GVHD, all of which create added potential for inter- and intra-patient variations in drug metabolism as well as drug interactions. Polymorphism is common in genes encoding pathway components of antifungal drug metabolism such as enzymes (cytochrome P450 (CYP450), glutathione S-transferase, N-acetyltransferase and uridine 5'-diphospho-glucuronosyltransferase), uptake transporters (organic cationic transporter, novel organic cationic transporter, organic anion transporter protein (OATP), organic anion transport (OAT), and peptide tranporter) and efflux transporters (breast cancer resistance protein, bile sale export pump (BSEP), multidrug and toxin extrusion type transporter, multidrug resistance protein (MRP), OAT, permeability glycoprotein (P-gp), and urate transporter). Specific polymorphisms may be generalised throughout a population or largely confined to ethnic groups. CYP450 enzymes, especially 2C9 and 2C19, exhibit extensive polymorphism and are central to the metabolism of azole antifungals and their interactions with other drugs including calcineurin inhibitors, cytotoxics and benzodiazepines. Polymorphism may ultimately affect drug efficacy: CYP2C19 variation leads to a fivefold variation in voriconazole levels between individuals. Anticipated routine provision of pharmacogenomic data in the future for new drugs, together with accumulating knowledge about established agents, challenge physicians to assimilate and apply that information to drug prescribing. Increasing availability of pharmacogenomic data may strengthen demand for rapid turn-around therapeutic drug monitoring of antifungal agents in HSCT recipients.
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PMID:Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics. 2178 68

Single nucleotide polymorphisms in drug-metabolizing genes may affect tacrolimus pharmacokinetics. Here, we investigated the influence of genotypes of CYP3A5, CYP2C19, and POR on the concentration/dose (C/D) ratio of tacrolimus and episodes of acute graft-versus-host disease (GVHD) in Japanese recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Thirty-six patients receiving the first HSCT using tacrolimus-based GVHD prophylaxis were enrolled with written informed consent. During continuous intravenous infusion, HSCT recipients carrying the CYP3A5*1 allele, particularly those with at least one POR*28 allele, had a significantly lower tacrolimus C/D ratio throughout all three post-HSCT weeks compared to that in recipients with POR*1/*1 (p < 0.05). The CYP3A5*3/*3 genotype and the concomitant use of voriconazole were independent predictors of an increased tacrolimus C/D ratio during the switch from continuous intravenous infusion to oral administration (p < 0.05). In recipients receiving concomitant administration of voriconazole, our results suggest an impact of not only CYP3A5 and CYP2C19 genotypes, but also plasma voriconazole concentration. Although switching from intravenous to oral administration at a ratio of 1:5 was seemingly appropriate in recipients with CYP3A5*1, a lower conversion ratio (1:2-3) was appropriate in recipients with CYP3A5*3/*3. Our results suggest that CYP3A5, POR, and CYP2C19 polymorphisms are useful biomarkers for individualized dosage adjustment of tacrolimus in HSCT recipients.
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PMID:Impact of CYP3A5, POR, and CYP2C19 Polymorphisms on Trough Concentration to Dose Ratio of Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplantation. 3109 84