ABCB1 p.Gly449Ala
| Predicted by SNAP2: | A: D (80%), C: D (80%), D: D (91%), E: D (85%), F: D (91%), H: D (91%), I: D (91%), K: D (91%), L: D (91%), M: D (85%), N: D (80%), P: D (91%), Q: D (85%), R: D (91%), S: D (85%), T: D (85%), V: D (85%), W: D (91%), Y: D (91%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Toward individualized treatment: prediction of ant... Anticancer Drugs. 2007 Feb;18(2):111-26. Deeken JF, Figg WD, Bates SE, Sparreboom A
Toward individualized treatment: prediction of anticancer drug disposition and toxicity with pharmacogenetics.
Anticancer Drugs. 2007 Feb;18(2):111-26., [PMID:17159598]
Abstract [show]
A great deal of effort has been spent in defining the pharmacokinetics and pharmacodynamics of investigational and registered anticancer agents. Often, there is a marked variability in drug handling between individual patients, which contributes to variability in the pharmacodynamic effects of a given dose of a drug. A combination of physiological variables, genetic characteristics (pharmacogenetics) and environmental factors is known to alter the relationship between the absolute dose and the concentration-time profile in plasma. A variety of strategies are now being evaluated in patients with cancer to improve the therapeutic index of anticancer drugs by implementation of pharmacogenetic imprinting through genotyping or phenotyping individual patients. The efforts have mainly focused on variants in genes encoding the drug-metabolizing enzymes thiopurine S-methyltransferase, dihydropyrimidine dehydrogenase, members of the cytochrome P450 family, including the CYP2B, 2C, 2D and 3A subfamilies, members of the UDP glucuronosyltransferase family, as well as the ATP-binding cassette transporters ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein). Several of these genotyping strategies have been shown to have substantial impact on therapeutic outcome and should eventually lead to improved anticancer chemotherapy.
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178 Table 5 Ethnic frequency (%) of allelic variants in CYP2C9 Allelic variant SNPs Caucasians African-Americans Asians Hispanics Africans CYP2C9*2 C430T 6.8-13.2 1.0-2.5 0 8.0 CYP2C9*3 A1075C 4.3-15.9 0.5-1.25 0-2.2 6.0 CYP2C9*5 C1080G 0 1.7 CYP2C9*7 C55A 7.1 CYP2C9*8 G449A 6.7 7.1 CYP2C9*9 A752G 0.5 13.3 14.3 CYP2C9*11 C1003T 1 CYP2C9*12 C1465T 0.5 SNP, single nucleotide polymorphism. Sources: Caucasians [51-54], African Americans [52,54,55], Asians [52,56], Hispanics [57], Africans [52].
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ABCB1 p.Gly449Ala 17159598:178:266
status: NEW[hide] Ex Vivo Drug Susceptibility Testing and Molecular ... Antimicrob Agents Chemother. 2015 Aug;59(8):4631-43. doi: 10.1128/AAC.00366-15. Epub 2015 May 26. Chaorattanakawee S, Saunders DL, Sea D, Chanarat N, Yingyuen K, Sundrakes S, Saingam P, Buathong N, Sriwichai S, Chann S, Se Y, Yom Y, Heng TK, Kong N, Kuntawunginn W, Tangthongchaiwiriya K, Jacob C, Takala-Harrison S, Plowe C, Lin JT, Chuor CM, Prom S, Tyner SD, Gosi P, Teja-Isavadharm P, Lon C, Lanteri CA
Ex Vivo Drug Susceptibility Testing and Molecular Profiling of Clinical Plasmodium falciparum Isolates from Cambodia from 2008 to 2013 Suggest Emerging Piperaquine Resistance.
Antimicrob Agents Chemother. 2015 Aug;59(8):4631-43. doi: 10.1128/AAC.00366-15. Epub 2015 May 26., [PMID:26014942]
Abstract [show]
Cambodia's first-line artemisinin combination therapy, dihydroartemisinin-piperaquine (DHA-PPQ), is no longer sufficiently curative against multidrug-resistant Plasmodium falciparum malaria at some Thai-Cambodian border regions. We report recent (2008 to 2013) drug resistance trends in 753 isolates from northern, western, and southern Cambodia by surveying for ex vivo drug susceptibility and molecular drug resistance markers to guide the selection of an effective alternative to DHA-PPQ. Over the last 3 study years, PPQ susceptibility declined dramatically (geomean 50% inhibitory concentration [IC50] increased from 12.8 to 29.6 nM), while mefloquine (MQ) sensitivity doubled (67.1 to 26 nM) in northern Cambodia. These changes in drug susceptibility were significantly associated with a decreased prevalence of P. falciparum multidrug resistance 1 gene (Pfmdr1) multiple copy isolates and coincided with the timing of replacing artesunate-mefloquine (AS-MQ) with DHA-PPQ as the first-line therapy. Widespread chloroquine resistance was suggested by all isolates being of the P. falciparum chloroquine resistance transporter gene CVIET haplotype. Nearly all isolates collected from the most recent years had P. falciparum kelch13 mutations, indicative of artemisinin resistance. Ex vivo bioassay measurements of antimalarial activity in plasma indicated 20% of patients recently took antimalarials, and their plasma had activity (median of 49.8 nM DHA equivalents) suggestive of substantial in vivo drug pressure. Overall, our findings suggest DHA-PPQ failures are associated with emerging PPQ resistance in a background of artemisinin resistance. The observed connection between drug policy changes and significant reduction in PPQ susceptibility with mitigation of MQ resistance supports reintroduction of AS-MQ, in conjunction with monitoring of the P. falciparum mdr1 copy number, as a stop-gap measure in areas of DHA-PPQ failure.
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136 C580Y was most prevalent and was found in 66%, whereas R539T accounted for 15% and Y493H, N458Y, and G449A occurred at lower frequencies of 2.5%, 1.0%, and 0.2%, respectively.
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ABCB1 p.Gly449Ala 26014942:136:101
status: NEW