Displaying publications 41 - 60 of 65 in total

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  1. Effect of eurycomanone on cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 in vitro
    Pan Y, Tiong KH, Abd-Rashid BA, Ismail Z, Ismail R, Mak JW, et al.
    J Nat Med, 2014 Apr;68(2):402-6.
    PMID: 23881640 DOI: 10.1007/s11418-013-0794-8
    Eurycomanone, an active constituent isolated from Eurycoma longifolia Jack, was examined for modulatory effects on cytochrome P450 (CYP) isoforms CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 using in vitro assays. The IC50 value was determined to assess the potencies of modulation for each CYP isoform. Our results indicated that eurycomanone did not potently inhibit any of the CYP isoforms investigated, with IC50 values greater than 250 μg/ml. Hence there appears to be little likelihood of drug-herb interaction between eurycomanone or herbal products with high content of this compound and CYP drug substrates via CYP inhibition.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/metabolism*
  2. In vitro determination of the effect of Andrographis paniculata extracts and andrographolide on human hepatic cytochrome P450 activities
    Pan Y, Abd-Rashid BA, Ismail Z, Ismail R, Mak JW, Pook PC, et al.
    J Nat Med, 2011 Jul;65(3-4):440-7.
    PMID: 21365364 DOI: 10.1007/s11418-011-0516-z
    We investigated the effects of Andrographis paniculata (AP) extracts and andrographolide on the catalytic activity of three human cDNA-expressed cytochrome P450 enzymes: CYP2C9, CYP2D6 and CYP3A4. In vitro probe-based high performance liquid chromatography assays were developed to determine CYP2C9-dependent tolbutamide methylhydroxylation, CYP2D6-dependent dextromethorphan O-demethylation and CYP3A4-dependent testosterone 6β-hydroxylation activities in the presence and absence of AP extracts and andrographolide. Our results indicate that AP ethanol and methanol extracts inhibited CYP activities more potently than aqueous and hexane extracts across the three isoforms. Potent inhibitory effects were observed on CYP3A4 and CYP2C9 activities (K (i) values below 20 μg/ml). Andrographolide was found to exclusively but weakly inhibit CYP3A4 activity. In conclusion, data presented in this study suggest that AP extracts have the potential to inhibit CYP isoforms in vitro. There was, however, variation in the potency of inhibition depending on the extracts and the isoforms investigated.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/metabolism*
  3. Translational aspects of genetic factors in the prediction of drug response variability: a case study of warfarin pharmacogenomics in a multi-ethnic cohort from Asia
    Chan SL, Suo C, Lee SC, Goh BC, Chia KS, Teo YY
    Pharmacogenomics J, 2012 Aug;12(4):312-8.
    PMID: 21383771 DOI: 10.1038/tpj.2011.7
    Genetic markers displaying highly significant statistical associations with complex phenotypes may not necessarily possess sufficient clinical validity to be useful. Understanding the contribution of these markers beyond readily available clinical biomarkers is particularly important in pharmacogenetics. We demonstrate the utility of genetic testing using the example of warfarin in a multi-ethnic setting comprising of three Asian populations that are broadly representative of the genetic diversity for half of the population in the world, especially as distinct interethnic differences in warfarin dose requirements have been previously established. We confirmed the roles of three well-established loci (CYP2C9, VKORC1 and CYP4F2) in explaining warfarin dosage variation in the three Asian populations. In addition, we assessed the relationship between ethnicity and the genotypes of these loci, observing strong correlations at VKORC1 and CYP4F2. Subsequently, we established the additional utility of these genetic factors in predicting warfarin dose beyond ethnicity and clinical biomarkers through performing a series of systematic cross-validation analyses of the relative predictive accuracies of various fixed-dose regimen, clinical and genetic models. Through a pharmacogenetics model for warfarin, we show the importance of genetic testing beyond readily available clinical biomarkers in predicting dose requirements, confirming the role of genetic profiling in personalized medicine.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/genetics*
  4. Involvement of phenobarbital and SKF 525A in the hepatotoxicity of antifungal drugs itraconazole and fluconazole in rats
    Somchit N, Wong CW, Zuraini A, Ahmad Bustamam A, Hasiah AH, Khairi HM, et al.
    Drug Chem Toxicol, 2006;29(3):237-53.
    PMID: 16777703
    Itraconazole and fluconazole are potent wide spectrum antifungal drugs. Both of these drugs induce hepatotoxicity clinically. The mechanism underlying the hepatotoxicity is unknown. The purpose of this study was to investigate the role of phenobarbital (PB), an inducer of cytochrome P450 (CYP), and SKF 525A, an inhibitor of CYP, in the mechanism of hepatotoxicity induced by these two drugs in vivo. Rats were pretreated with PB (75 mg/kg for 4 days) prior to itraconazole or fluconazole dosing (20 and 200 mg/kg for 4 days). In the inhibition study, for 4 consecutive days, rats were pretreated with SKF 525A (50 mg/kg) or saline followed by itraconazole or fluconazole (20 and 200 mg/kg) Dose-dependent increases in plasma alanine aminotransferase (ALT), gamma-glutamyl transferase (gamma-GT), and alkaline phosphatase (ALP) activities and in liver weight were detected in rats receiving itraconazole treatment. Interestingly, pretreatment with PB prior to itraconazole reduced the ALT and gamma-GT activities and the liver weight of rats. No changes were observed in rats treated with fluconazole. Pretreatment with SKF 525A induced more severe hepatotoxicity for both itraconazole and fluconazole. CYP 3A activity was inhibited dose-dependently by itraconazole treatment. Itraconazole had no effects on the activity of CYP 1A and 2E. Fluconazole potently inhibited all three isoenzymes of CYP. PB plays a role in hepatoprotection to itraconazole-induced but not fluconazole-induced hepatotoxicity. SKF 525A enhanced the hepatotoxicity of both antifungal drugs in vivo. Therefore, it can be concluded that inhibition of CYP may play a key role in the mechanism of hepatotoxicity induced by itraconazole and fluconazole.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/metabolism
  5. The influence of CYP3A gene polymorphisms on cyclosporine dose requirement in renal allograft recipients
    Eng HS, Mohamed Z, Calne R, Lang CC, Mohd MA, Seet WT, et al.
    Kidney Int, 2006 May;69(10):1858-64.
    PMID: 16612333
    Cyclosporine is a substrate of cytochrome P-450 3A (CYP3A) subfamily of enzymes and characterized by a narrow therapeutic range with wide interindividual variation in pharmacokinetics. A few single-nucleotide polymorphisms detected in CYP3A genes have been shown to correlate significantly with the CYP3A protein expression and activity. We therefore postulated that these polymorphisms could be responsible for some of the interindividual variation in cyclosporine pharmacokinetics. The objective of our study is to determine correlation if any between single-nucleotide polymorphisms of CYP3A5 and CYP3AP1 on cyclosporine dose requirement and concentration-to-dose ratio in renal allograft recipients. Cyclosporine-dependent renal allograft recipients were genotyped for CYP3A5 A6986G and CYP3AP1 G-44A. The cyclosporine dosages prescribed and the corresponding cyclosporine trough levels for each patient were recorded so that cyclosporine dose per weight (mg/kg/day) and concentration-to-dose ratio (C(0)/D, whereby C(0) is trough level and D is daily dose per weight) could be calculated. A total of 67 patients were recruited for our study. The dose requirement for 1, 3, and 6 months post-transplantation ranged 2.3-11.4, 1.0-9.0, and 1.4-7.2 mg/kg/day, respectively. Patients with *1*1*1*1 (n=5) CYP3A5- and CYP3AP1-linked genotypes needed higher dose of cyclosporine compared to patients with *1*3*1*3 (n = 27) and *3*3*3*3 (n = 33) linked genotypes in months 3 and 6 post-transplantation (P < 0.016). The identification of patients with *1*1*1*1 by CYP3A5 and CYP3AP1 genotyping may have a clinically significant and positive impact on patient outcome with reduced rejection rate by providing pretransplant pharmacogenetic information for optimization of cyclosporine A dosing.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/genetics*
  6. Itraconazole- and fluconazole-induced toxicity in rat hepatocytes: a comparative in vitro study
    Somchit N, Hassim SM, Samsudin SH
    Hum Exp Toxicol, 2002 Jan;21(1):43-8.
    PMID: 12046723
    This current study was to investigate the in vitro cytotoxicity of rat hepatocytes induced by the antifungal drugs, itraconazole and fluconazole. Both antifungal drugs caused dose-dependent cytotoxicity. In vitro incubation of hepatocytes with itraconazole revealed significantly higher lactate dehydrogenase (LDH) leakage when compared to fluconazole. Phenobarbital pretreated hepatocytes contained significantly higher total cytochrome P450 content than the control hepatocytes. P450 content was reduced approximately 30% for both types of hepatocytes after 6 hours incubation. Interestingly, cytotoxicity of itraconazole was reduced significantly by phenobarbital pretreatment. Phenobarbital did not have any effect on the cytotoxicity induced by fluconazole. These results demonstrate the in vitro toxicity of hepatocytes induced by itraconazole and fluconazole that were expressed in a dose- and time-dependent manner. Phenobarbital plays a role in the cytoprotection of hepatocytes to itraconazole-induced but not fluconazole-induced cytotoxicity in vitro.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/biosynthesis
  7. Characterization and biological properties of NanoCUR formulation and its effect on major human cytochrome P450 enzymes
    Shamsi S, Chen Y, Lim LY
    Int J Pharm, 2015 Nov 10;495(1):194-203.
    PMID: 26319630 DOI: 10.1016/j.ijpharm.2015.08.066
    Curcumin (CUR) has been formulated into a host of nano-sized formulations in a bid to improve its in vivo solubility, stability and bioavailability. The aim of this study was to investigate whether the encapsulation of CUR in nanocarriers would impede its biological interactivity, specifically its potential anti-cancer adjuvant activity via the modulation of CYP enzymes in vitro. NanoCUR, a micellar dispersion prepared via a thin film method using only Pluronic F127 as excipient, was amenable to lyophilization, and retained its nano-sized spherical dimensions (17-33 nm) upon reconstitution with water followed by dilution to 5 μM with HBSS or EMEM. NanoCUR was a weaker cytotoxic agent compared to CUR in solution (sCUR), affecting HepG2 cell viability only when the incubation time was prolonged from 4h to 48 h. Correlation with 2h uptake data suggests this was due to a lower cellular uptake rate of CUR from NanoCUR than from sCUR. The poorer CUR accessibility might also account for NanoCUR being a weaker inhibitor of CYP2C9 and CYP2D6 than sCUR. NanoCUR was, however, 1.76-fold more potent against the CYP3A4 (IC50 5.13 ± 0.91 μM) metabolic function. The higher activity against CYP3A4 might be attributed to the synergistic action of Pluronic F127, since the blank micellar dispersion also inhibited CYP3A4 activity. Both sCUR and NanoCUR had no effect on the CYP3A4 mRNA levels in the HepG2 cells. NanoCUR therefore, maintained most of the biological activities of CUR in vitro, albeit at a lower potency and response rate.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/biosynthesis*
  8. Curcumin, Piperine, and Capsaicin: A Comparative Study of Spice-Mediated Inhibition of Human Cytochrome P450 Isozyme Activities
    Shamsi S, Tran H, Tan RS, Tan ZJ, Lim LY
    Drug Metab. Dispos., 2017 01;45(1):49-55.
    PMID: 27821437
    Inhibition of cytochrome P450 (P450) enzymes (CYP) has been shown to lower the metabolism of drugs that are P450 substrates and to consequently alter their pharmacokinetic profiles. Curcumin (CUR), piperine (PIP), and capsaicin (CAP) are spice components (SC) that inhibit the activities of a range of P450 enzymes, but the selection of which SC to be prioritized for further development as an adjuvant will depend on the ranking order of the inhibitory potential of the SCs on specific P450 isozymes. We used common human recombinant enzyme platforms to provide a comparative evaluation of the inhibitory activities of CUR, PIP, and CAP on the principal drug-metabolizing P450 enzymes. SC-mediated inhibition of CYP3A4 was found to rank in the order of CAP (IC501.84 ± 0.71 µM) ∼ PIP (2.12 ± 0.45 µM) > CUR (11.93 ± 3.49 µM), while CYP2C9 inhibition was in the order of CAP (11.95 ± 4.24 µM) ∼ CUR (14.58 ± 4.57 µM) > PIP (89.62 ± 9.17 µM). CAP and PIP were significantly more potent inhibitors of CYP1A2 (IC502.14 ± 0.22 µM and 14.19 ± 4.15 µM, respectively) than CUR (IC50> 100 µM), while all three SCs exhibited weak activity toward CYP2D6 (IC5095.42 ± 12.09 µM for CUR, 99.99 ± 5.88 µM for CAP, and 110.40 ± 3.23 µM for PIP). Of the three SCs, CAP thus has the strongest potential for further development into an inhibitor of multiple CYPs for use in the clinic. Data from this study are also useful for managing potential drug-SC interactions.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/metabolism*
  9. Effect of phenobarbitone treatment against signal grass (Brachiaria decumbens) toxicity in sheep
    Hasiah AH, Elsheikh HA, Abdullah AS, Khairi HM, Rajion MA
    Vet J, 2000 Nov;160(3):267-72.
    PMID: 11061964
    The effect of phenobarbitone against signal grass (Brachiaria decumbens) toxicity was studied in 26 male crossbred sheep. Grazing on signal grass significantly decreased the concentration of cytochrome P-450 and the activity of drug metabolizing enzymes, viz. aminopyrine-N-demethylase, aniline-4-hydroxylase, UDP- glucuronyltransferase and glutathione-S-transferase in liver and kidneys of affected sheep.Oral administration of phenobarbitone (30 mg/kg body weight) for five consecutive days before grazing on B. decumbens pasture, and thereafter, for three consecutive days every two weeks, resulted in significant increases in hepatic and renal activities of drug-metabolizing enzymes. The induction of drug metabolizing activity in sheep grazing on signal grass group was found to be lower than in animals given phenobarbitone alone. Induction by phenobarbitone provided a degree of protection against the toxic effects of B. decumbens as indicated by the delay in the appearance of signs of toxicity. Furthermore, these were much milder compared to those in the sheep not treated with phenobarbitone. The present study suggests that phenobarbitone-type cytochrome P-450 isoenzyme-induction may increase resistance against signal grass (B. decumbens) toxicity in sheep.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/biosynthesis
  10. Fulltext Pharmacogenomics biomarkers for personalized methadone maintenance treatment: The mechanism and its potential use
    Ramli FF
    Bosn J Basic Med Sci, 2021 Apr 01;21(2):145-154.
    PMID: 32841585 DOI: 10.17305/bjbms.2020.4897
    Methadone has a wide pharmacokinetic interindividual variability, resulting in unpredicted treatment response. Pharmacogenomic biomarkers seem promising for personalized methadone maintenance treatment. The evidence supports the use of ABCB1 single-nucleotide polymorphism (SNP) 1236C>T with genotypes C/T or C/C (Jewish) and haplotypes AGCTT carrier, AGCGC heterozygote, or non-carrier (Caucasian), which have a predicted lower methadone dose requirement. In contrast, ABCB1 SNP 1236C>T with genotype T/T (Jewish); haplotypes AGCGC homozygote, AGCTT non-carrier (Caucasian), and ABCB1 3435C>T variant carrier; and haplotypes CGT, TTC, and TGT (Han Chinese) have a predicted higher methadone dose. For methadone plasma levels, ABCB1 diplotype non-CGC/TTT (Malay) predicted lower, and diplotype CGC/TTT (Malay), 3435C>T allelic carrier, haplotypes (CGT, TTC, TGT) (Han Chinese) predicted higher methadone levels. In terms of metabolism biomarkers, a lower methadone requirement was related to carriers of CYP2B6 genotypes *4(G/G) and *9(T/T) among Jewish patients, CYP2B6*9 genotype (T/T) and haplotypes (TA/TG); and CYP2C19 (*2/*2,*2/*3, and *3/*3; Han Chinese). Higher methadone dose was observed in CYP2C19*1 allelic carriers (Han Chinese) and CYP2D6 ultrarapid metabolizer (Caucasian). Lower methadone levels were reported in CYP2B6 SNPs, haplotypes TTT, and AGATAA (Han Chinese), CYP2C19 genotype *1/*1 (Han Chinese), allelic carrier *1xN (Caucasian), and CYP3A4 genotype *1/*1 (Caucasian). Carriers of CYP2B6 genotype *6/*6 (Caucasian), CYP2B6 haplotypes ATGCAG and ATGCTG (Han Chinese), and CYP3A4 genotype *1/*1B (Caucasian) had predicted higher methadone plasma levels. Specific pharmacokinetics biomarkers have potential uses for personalized methadone treatment in specific populations.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/genetics*
  11. Evaluation of Herb-Drug Interaction of Synacinn™ and Individual Biomarker through Cytochrome 450 Inhibition Assay
    Ab Rahman NS, Abd Majid FA, Abd Wahid ME, Zainudin AN, Zainol SN, Ismail HF, et al.
    Drug Metab Lett, 2018;12(1):62-67.
    PMID: 29542427 DOI: 10.2174/1872312812666180314112457
    BACKGROUND: SynacinnTM contains five standardized herbal extracts of Orthosiphon Stamineus (OS), Syzygium polyanthum (SZ), Curcuma xantorrizza (CX), Cinnamomum zeylanicum (CZ) and Andrographis paniculata (AP) and is standardized against phytochemical markers of rosmarinic acid, gallic acid, curcumin, catechin and andrographolide respectively. This herbal medicine has been used as health supplement for diabetes. SynacinnTM is recommended to be consumed as supplement to the diabetic drugs. However, herb-drug interaction of SynacinnTM polyherbal with present drugs is unknown.

    METHODS: This study was designed to investigate the effect of SynacinnTM and its individual biomarkers on drug metabolizing enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (Midazolam), CYP3A4 (Testosteron)), to assess its herb-drug interaction potential through cytochrome P450 inhibition assay. This study was conducted using liquid chromatography- tandem mass spectroscopy (LC-MS/MS) using probe substrates using human liver microsomes against CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (Midazolam) and CYP3A4 (Testosteron).

    RESULTS: Result showed that SynacinnTM at maximum concentration (5000 µg/ml) 100% inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 (Midazolam) and CYP3A4 (Testosteron). IC50 values determined were 0.23, 0.60, 0.47, 0.78, 1.23, 0.99, 1.01, and 0.91 mg/ml for CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4 (midazolam) and 3A4 (testosterone), respectively. Meanwhile, all individual biomarkers showed no, less or moderate inhibitory effect towards all the tested CYP450 except for curcumin that showed inhibition of CYP2C8 (91%), CYP2C9 (81%) and CYP2C19 (72%) at 10µM.

    CONCLUSION: Curcumin was found to be an active constituent that might contribute to the inhibition of SynacinnTM against CYP2C8, CYP2C9 and CYP2C19. It can be suggested that SynacinnTM can be consumed separately from a drug known to be metabolized by all tested CYP450 enzymes.

    Matched MeSH terms: Cytochrome P-450 Enzyme System/metabolism*
  12. Reduced expression of prostacyclin synthase and nitric oxide synthase in subcutaneous arteries of type 2 diabetic patients
    Safiah Mokhtar S, M Vanhoutte P, W S Leung S, Imran Yusof M, Wan Sulaiman WA, Zaharil Mat Saad A, et al.
    Tohoku J Exp Med, 2013 11;231(3):217-22.
    PMID: 24225501
    Diabetic endothelial dysfunction is characterized by impaired endothelium-dependent relaxation. In this study, we measured the expression of endothelial nitric oxide synthase (eNOS), cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), prostacyclin synthase (PGIS), and prostacyclin receptor (IP) in subcutaneous arteries of type-2 diabetic and non-diabetic patients. Subcutaneous arteries were dissected from tissues from seven diabetics (4 males and 3 females) and seven non-diabetics (5 males and 2 females) aged between 18 to 65 years, who underwent lower limb surgical procedures. Diabetics had higher fasting blood glucose compared to non-diabetics, but there were no differences in blood pressure, body mass index and age. Patients were excluded if they had uncontrolled hypertension, previous myocardial infarction, coronary heart disease, renal or hepatic failure and tumor. The relative expression levels of eNOS, COX-1, COX-2, PGIS and IP receptor were determined by Western blotting analysis, normalized with the β-actin level. Increased expression of COX-2 was observed in subcutaneous arteries of diabetics compared to non-diabetics, whereas the expression levels of eNOS and PGIS were significantly lower in diabetics. There were no significant differences in expression levels of COX-1 and IP receptor between the two groups. Immunohistochemical study of subcutaneous arteries showed that the intensities of eNOS and PGIS staining were lower in diabetics, with higher COX-2 staining. In conclusion, type-2 diabetes is associated with higher COX-2 expression, but lower eNOS and PGIS expression in subcutaneous arteries. These alterations may lead to impaired endothelium-dependent vasodilatation, and thus these proteins may be potential targets for protection against the microvascular complications of diabetes.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/metabolism*
  13. Fulltext Effects of cytochrome p450 inhibitors on itraconazole and fluconazole induced cytotoxicity in hepatocytes
    Somchit N, Ngee CS, Yaakob A, Ahmad Z, Zakaria ZA
    J Toxicol, 2009;2009:912320.
    PMID: 20130764 DOI: 10.1155/2009/912320
    Itraconazole and fluconazole have been reported to induce hepatotoxicity in patients. The present study was designed to investigate the role of cytochrome P450 inhibitors, SKF 525A, and curcumin pretreatment on the cytotoxicity of antifungal drugs fluconazole and itraconazole. For 3 consecutive days, female rats were administered daily SKF 525A or curcumin (5 and 25 mg/kg). Control rats received an equivalent amount of dosed vehicle. The animals were anaesthetized 24 hours after receiving the last dose for liver perfusion. Hepatocytes were then exposed to various concentrations of antifungal drugs. In vitro incubation of hepatocytes with itraconazole revealed significantly lower viability when compared to fluconazole as assessed by lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase activities. The cytotoxicity of itraconazole was enhanced when incubated with hepatocytes pretreated with SKF 525A. SKF 525A had no effects on the cytotoxicity of fluconazole. Curcumin failed to either increase or decrease the cytotoxicity of both antifungal drugs. ATP levels also showed significant decrease in both itraconazole and fluconazole incubated hepatocytes. However, SKF 525A pretreated hepatocytes had significantly lower ATP levels after itraconazole incubations. Collectively, these results confirm the involvement of cytochrome P450 in the cytoprotection in itraconazole induced hepatocyte toxicity. Differences of the effects of SKF 525A on the cytotoxicity induced by itraconazole and fluconazole may be due to the differences on the metabolism of each antifungal drug in vivo.
    Matched MeSH terms: Cytochrome P-450 Enzyme System
  14. Fulltext Treatment of allergic rhinitis and urticaria: a review of the newest antihistamine drug bilastine
    Wang XY, Lim-Jurado M, Prepageran N, Tantilipikorn P, Wang de Y
    Ther Clin Risk Manag, 2016;12:585-97.
    PMID: 27110120 DOI: 10.2147/TCRM.S105189
    Allergic rhinitis and urticaria are common allergic diseases that may have a major negative impact on patients' quality of life. Bilastine, a novel new-generation antihistamine that is highly selective for the H1 histamine receptor, has a rapid onset and prolonged duration of action. This agent does not interact with the cytochrome P450 system and does not undergo significant metabolism in humans, suggesting that it has very low potential for drug-drug interactions, and does not require dose adjustment in renal impairment. As bilastine is not metabolized and is excreted largely unchanged, hepatic impairment is not expected to increase systemic exposure above the drug's safety margin. Bilastine has demonstrated similar efficacy to cetirizine and desloratadine in patients with seasonal allergic rhinitis and, in a Vienna Chamber study, a potentially longer duration of action than fexofenadine in patients with asymptomatic seasonal allergic rhinitis. It has also shown significant efficacy (similar to that of cetirizine) and safety in the long-term treatment of perennial allergic rhinitis. Bilastine showed similar efficacy to levocetirizine in patients with chronic spontaneous urticaria and can be safely used at doses of up to fourfold higher than standard dosage (80 mg once daily). The fourfold higher than standard dose is specified as an acceptable second-line treatment option for urticaria in international guidelines. Bilastine is generally well tolerated, both at standard and at supratherapeutic doses, appears to have less sedative potential than other second-generation antihistamines, and has no cardiotoxicity. Based on its pharmacokinetic properties, efficacy, and tolerability profile, bilastine will be valuable in the management of allergic rhinitis and urticaria.
    Matched MeSH terms: Cytochrome P-450 Enzyme System
  15. Cytochrome P450 genotype-guided drug therapies: An update on current states
    Dong AN, Tan BH, Pan Y, Ong CE
    Clin Exp Pharmacol Physiol, 2018 10;45(10):991-1001.
    PMID: 29858511 DOI: 10.1111/1440-1681.12978
    Over the past 2 decades, knowledge of the role and clinical value of pharmacogenetic markers has expanded so that individualized pre-emptive therapy based on genetic background of patients could be within reach for clinical implementation. This is evidenced from the frequent updating of drug labels that incorporates pharmacogenetic information (where compelling data become available) by the regulatory agencies (such as the US FDA), and the periodical publication of guidelines of specific therapeutic recommendations based on the results of pharmacogenetic tests by the pharmacogenetics working groups or consortiums of professional bodies. Clinical relevance of the cytochrome P450 (CYP) polymorphism related to dose, effectiveness and/or toxicity of key drugs are presented in this review, including that of warfarin, clopidogrel, tricyclic antidepressants, and proton pump inhibitors. Prospect for routine clinical application of CYP genotyping before prescribing drugs is still currently unclear due to challenges and barriers associated with availability of well-defined and validated pharmacogenetic studies, the interpretation, result reporting and potential error of genotype testing, involvement of non-genetic factors, and other patient's demographic and disease conditions. Further studies to provide additional supporting clinical data and acceleration of pharmacogenetic testing standards and techniques should help improve the evidence base needed for clinical utility and hence move the implementation of genotype-guided therapy in clinical practice a step closer to reality.
    Matched MeSH terms: Cytochrome P-450 Enzyme System
  16. Fulltext A minireview of CYP2C9 and CYP2C19 single nucleotide polymorphisms (SNPs) among Malaysian populations
    Rosdi R.A., Yusoff S., Mohd Yusoff N., Ismail R., Tan, C.S., Musa N.
    Journal of Biomedical and Clinical Sciences, 2017;2(1):47-52.
    MyJurnal
    It has been recognized extensively that studies of pharmacogenetics provide massive examples of causal relationship between genotypes and drug effectiveness to account for interindividual phenotypic variations in drug therapy. In most cases, cytochrome P450 (CYP) polymorphisms are one of the major variables that affecting those drug plasma concentration, drug detoxification and drug activation in humans. Thus, understanding of CYP polymorphisms can be crucially valuable in order to allow early and more accurate drug dosage prediction and improve the drug response accordingly. Despite the high level of homologous amino acid sequences, CYP2C9 and CYP2C19 genes are among the most important CYP genes which metabolize a wide range of clinically therapeutic drugs. Several critical reviews have been published relating to the aforementioned genes. However, this minireview aims to systematically merge reported studies on the SNPs frequencies of both genes concentrating only on Malaysian population. It is hoped that, the minireview can be an opener for new opportunities to reevaluate the evidence on the prevalence of CYP2C genes as a potential genetic factor influencing a particular drug efficacy and safety among Malaysian. Such evaluation can be developed to the next level of early prediction of better and specific drug treatment, thereby improving the drug response while helping the government in minimising the drug expenditures.
    Matched MeSH terms: Cytochrome P-450 Enzyme System
  17. Fulltext An update on HLA alleles as pharmacogenetic markers for antiepileptic drug-induced cutaneous adverse reaction
    Then, Sue-Mian, Azman Ali Raymond
    Neuroscience Research Notes, 2019;2(2):1-17.
    MyJurnal
    Epilepsy is a common neurological disorder affecting approximately 50 million people worldwide. Antiepileptic drugs (AEDs) are commonly used to treat the disease depending, mainlyon the type of seizure. However, the useof AEDs mayalso lead to cutaneous adverse drug reactions (cADR) such as toxic epidermal necrolysis (TEN), Stevens-Johnsonsyndrome (SJS), exfoliative dermatitis (ED) and drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS), which are unwanted comorbidities in epilepsy. It was first discoveredthat the HLA-B*15:02 allele was strongly associatedwith carbamazepine(CBZ)-induced SJS/TEN amongHan Chinese and this ledto the discovery of other HLAallelesand cytochrome P450 (CYP) genes that were significantly associatedwith various AED-inducedcADRsacross variouspopulations. This mini-reviewis an update on the latest findings ofthe involvement of various HLA alleles and CYP alleles in cADRs caused by CBZ, phenytoin (PHT), oxcarbazepine (OXC) and lamotrigine(LTG) in different case-control studies around the world. From our review, we found that CBZ-and PHT-induced cADRsweremore commonly reportedthan the other AEDs.Therefore,there were morerobust pharmacogenetics studies related to these AEDs. OXC-and LTG-induced cADRswereless commonly reported,and somore studies are needed to validate the reported association of the newer reported HLA alleles with theseAEDs. It is also importantto considerthe allelic frequency within a given population before concludingthe use of thesealleles as genetic markers to prevent AED-induced cADR. Overall, the current body of research pointto a combination of alleles as a better pharmacogenetic marker comparedto the use of a single gene as a genetic marker for AED-induced cADR.
    Matched MeSH terms: Cytochrome P-450 Enzyme System
  18. Fulltext Polypharmacy in a nine year old boy with Attention Deficit Hyperactivity Disorder and Tourette Syndrome: what worsened the tics?
    Wan Salwina Wan Ismail, Aili Hanim Hashim, Kaur, Manveen, Choo, Shell Pin, Fairuz Nazri Abdul Rahman
    Malaysian Journal of Medicine and Health Sciences, 2014;10(2):79-81.
    MyJurnal
    Attention Deficit Hyperactivity Disorder(ADHD) and Tourrete Syndrome(TS) commonly
    co-occur, imposing a special challenge in the management. Case report: This is a case of a nine year old boy with ADHD and TS, who had been on methylphenidate, risperidone, fluvoxamine and atomoxetine, alone and in combination. Tics worsened with methylphenidate but improved after its withdrawal, and the addition of risperidone and fluvoxamine. Later, atomoxetine was added which worsened the tics, even when it was removed. Significant improvement in the tics were only obvious when fluvoxamine was taken off. Discussion: The possible roles of dopamine and serotonin neurotransmission, and metabolism of cytochrome P450 D26 in the pathophysiology were discussed. Conclusion: The use of multiple medications need cautious consideration and monitoring in a child patient to avoid unwanted complications and risks.
    Matched MeSH terms: Cytochrome P-450 Enzyme System
  19. KRT13, FAIM2 and CYP2W1 mRNA expression in oral squamous cell carcinoma patients with risk habits
    Hartanto FK, Karen-Ng LP, Vincent-Chong VK, Ismail SM, Mustafa WM, Abraham MT, et al.
    Asian Pac J Cancer Prev, 2015;16(3):953-8.
    PMID: 25735388
    BACKGROUND: Expression of KRT13, FAIM2 and CYP2W1 appears to be influenced by risk habits, thus exploring the associations of these genes in oral squamous cell cancer (OSCC) with risk habits, clinico-pathological parameters and patient survival may be beneficial in identifying relevant biomarkers with different oncogenic pathways.

    MATERIALS AND METHODS: cDNAs from 41 OSCC samples with and without risk habits were included in this study. Quantitative real-time PCR was used to analyze KRT13, FAIM2 and CYP2W1 in OSCC. The housekeeping gene (GAPDH) was used as an endogenous control.

    RESULTS: Of the 41 OSCC samples, KRT13 was down-regulated in 40 samples (97.6%), while FAIM2 and CYP2W1 were down-regulated in 61.0% and 48.8%, respectively. Overall, there were no associations between KRT13, FAIM2 and CYP2W1 expression with risk habits, selected socio-demographic and clinico-pathological parameters and patient survival.

    CONCLUSIONS: Although this study was unable to show significance, there were some tendencies in the associations of KRT13, FAIM2 and CYP2W1 expression in OSCC with selected clinic-pathological parameters and survival.

    Matched MeSH terms: Cytochrome P-450 Enzyme System/genetics*
  20. Fulltext Inhibition of human cytochrome P450 enzymes by Bacopa monnieri standardized extract and constituents
    Ramasamy S, Kiew LV, Chung LY
    Molecules, 2014 Feb 24;19(2):2588-601.
    PMID: 24566323 DOI: 10.3390/molecules19022588
    Bacopa monnieri and the constituents of this plant, especially bacosides, possess various neuropharmacological properties. Like drugs, some herbal extracts and the constituents of their extracts alter cytochrome P450 (CYP) enzymes, causing potential herb-drug interactions. The effects of Bacopa monnieri standardized extract and the bacosides from the extract on five major CYP isoforms in vitro were analyzed using a luminescent CYP recombinant human enzyme assay. B. monnieri extract exhibited non-competitive inhibition of CYP2C19 (IC50/Ki = 23.67/9.5 µg/mL), CYP2C9 (36.49/12.5 µg/mL), CYP1A2 (52.20/25.1 µg/mL); competitive inhibition of CYP3A4 (83.95/14.5 µg/mL) and weak inhibition of CYP2D6 (IC50 = 2061.50 µg/mL). However, the bacosides showed negligible inhibition of the same isoforms. B. monnieri, which is orally administered, has a higher concentration in the gut than the liver; therefore, this herb could exhibit stronger inhibition of intestinal CYPs than hepatic CYPs. At an estimated gut concentration of 600 µg/mL (based on a daily dosage of 300 mg/day), B. monnieri reduced the catalytic activities of CYP3A4, CYP2C9 and CYP2C19 to less than 10% compared to the total activity (without inhibitor = 100%). These findings suggest that B. monnieri extract could contribute to herb-drug interactions when orally co-administered with drugs metabolized by CYP1A2, CYP3A4, CYP2C9 and CYP2C19.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/metabolism
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