Lanchote Vera Lucia, Almeida Roque, Barral Aldina, Barral-Netto Manoel, Marques Maria Paula, Moraes Natália V, da Silva Angela M, Souza Tania M V, Suarez-Kurtz Guilherme
Laboratório de Farmacocinética e Metabolismo, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Ribeirão Preto, São Paulo, Brazil.
Universidade Federal de Sergipe, Hospital Universitário, Aracaju, Sergipe, Brazil.
Br J Clin Pharmacol. 2015 Nov;80(5):1160-8. doi: 10.1111/bcp.12677. Epub 2015 Jul 2.
The aim of the present study was to investigate the impact of human visceral leishmaniasis (VL) and curative chemotherapy on the activity of cytochrome P450 (CYP) 3A, CYP2C9 and CYP2C19 in patients from an endemic region in Brazil.
Adult patients with parasitologically confirmed VL were given a CYP phenotyping cocktail, comprising midazolam, omeprazole and losartan, immediately before (Study phase 1), 2-3 days (phase 2) and 3-6 months (phase 3) after curative VL chemotherapy. CYP activity was assessed by the apparent clearance of midazolam (CYP3A), omeprazole/5-hydroxyomeprazol ratio in plasma (CYP2C19) and losartan/E3174 ratio in urine (CYP2C9).
Mean values (95% confidence interval) in phases 1, 2 and 3 were, respectively: log apparent midazolam clearance, 1.21 (1.10-1.31), 1.45 (1.32-1.57) and 1.35 (1.26-1.44) ml min(-1) kg(-1) ; omeprazole/5-hydroxyomeprazole ratio, 0.78 (0.61-0.94), 0.45 (0.27-0.63) and 0.37 (0.20-0.55); losartan/E3174 ratio, 0.66 (0.39-0.92), 0.35 (0.20-0.50) and 0.35 (0.16-0.53). Analysis of variance revealed significant differences in CYP3A (P = 0.018) and CYP2C19 (P = 0.008), but not CYP2C9 (P = 0.11) phenotypic activity, across the three study phases.
The phenotypic activities of CYP3A4 and CYP2C19 were significantly reduced during acute VL compared with post-chemotherapy. We propose that increased plasma concentrations of proinflammatory cytokines during active disease account for the suppression of CYP activity. The failure to detect significant changes in CYP2C9 activity in the overall cohort may reflect differential effects of the inflammatory process on the expression of CYP isoforms, although the possibility of insufficient statistical power cannot be dismissed.
本研究旨在调查人类内脏利什曼病（VL）及根治性化疗对巴西某流行地区患者细胞色素P450（CYP）3A、CYP2C9和CYP2C19活性的影响。
经寄生虫学确诊的成年VL患者在根治性VL化疗前（研究阶段1）、化疗后2 - 3天（阶段2）和3 - 6个月（阶段3）立即服用一种CYP表型分析混合剂，该混合剂包含咪达唑仑、奥美拉唑和氯沙坦。通过咪达唑仑的表观清除率（CYP3A）、血浆中奥美拉唑/5 - 羟基奥美拉唑比值（CYP2C19）和尿液中氯沙坦/E3174比值（CYP2C9）评估CYP活性。
阶段1、2和3的平均值（95%置信区间）分别为：log表观咪达唑仑清除率，1.21（1.10 - 1.31）、1.45（1.32 - 1.57）和1.35（1.26 - 1.44）ml·min⁻¹·kg⁻¹；奥美拉唑/5 - 羟基奥美拉唑比值，0.78（0.61 - 0.94）、0.45（0.27 - 0.63）和0.37（0.20 - 0.55）；氯沙坦/E3174比值，0.66（0.39 - 0.92）、0.35（0.20 - 0.50）和0.35（0.16 - 0.53）。方差分析显示，在三个研究阶段中，CYP3A（P = 0.018）和CYP2C19（P = 0.008）的表型活性存在显著差异，但CYP2C9（P = 0.11）的表型活性无显著差异。
与化疗后相比，急性VL期间CYP3A4和CYP2C19的表型活性显著降低。我们认为，疾病活动期间促炎细胞因子血浆浓度升高导致了CYP活性的抑制。在整个队列中未检测到CYP2C9活性的显著变化，这可能反映了炎症过程对CYP同工酶表达的不同影响，尽管不能排除统计功效不足的可能性。
