Ethambutol plasma and intracellular pharmacokinetics: A pharmacogenetic study

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• 作者：Giovanna Fatigusop>1p> ; Sarah Allegrap> ; p>p>1p>p> ; p>p>sarah.allegra@gmail.com" class="auth_mail" title="E-mail the corresponding authorp> ; Andrea Calcagno ; Lorena Baietto ; Ilaria Motta ; Fabio Favata ; Jessica Cusato ; Stefano Bonora ; Giovanni Di Perri ; Antonio D&rsquo ; Avolio
• 关键词：Ethambutol
• 刊名：International Journal of Pharmaceutics
• 出版年：2016
• 出版时间：30 January 2016
• 年：2016
• 卷：497
• 期：1-2
• 页码：287-292
• 全文大小：434 K

文摘

We evaluated ethambutol plasma and intracellular pharmacokinetic according to single nucleotide polymorphisms in ABCB1, OATP1B1, PXR, VDR, CYP24A1 and CYP27B1 genes. Mycobacterium tubercolosis infected patients were enrolled. Standard weight-adjusted antitubercular treatment was administered intravenously for 2 weeks and then orally. Allelic discrimination was performed by real-time PCR. Ethambutol plasma and intracellular concentrations were measured by UPLC-MS/MS methods. Twenty-four patients were included. Considering weeks 2 and 4, median plasma C_trough were 73 ng/mL and 247 ng/mL, intracellular C_trough were 16,863 ng/mL and 13,535 ng/mL, plasma C_max were 5627 ng/mL and 2229 ng/mL, intracellular C_max were 133,830 ng/mL and 78,544 ng/mL. At week 2, ABCB1 3435 CT/TT (p = 0.023) and CYP24A1 8620 AG/GG (p = 0.030) genotypes for plasma C_trough, BsmI AA (p = 0.036) for intracellular C_trough and BsmI AA (p < 0.001) and ApaI AA (p = 0.048) for intracellular C_max, remained in linear regression analysis as predictive factors. Concerning week 4 only ABCB1 3435 CT/TT (p = 0.035) and Cdx2 AG/GG (p = 0.004) genotypes for plasma C_trough and BsmI AA (p = 0.028) for plasma C_max were retained in final regression model. We reveal, for the first time, the possible role of single nucleotide polymorphisms on ethambutol plasma and intracellular concentrations; this may further the potential use of pharmacogenetic for tailoring antitubercular treatment.