Impact of visceral leishmaniasis and curative chemotherapy on cytochrome P450 activity in Brazilian patients

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2016-04-11T19:37:16Z No. of bitstreams: 1 Lanchote, VL. Impact of visceral....pdf: 1105142 bytes, checksum: bbbaf0c963858cd545018a3daf83495d (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2016-04-12T13:12:51Z (GMT) No. of bitstreams: 1 Lanchote, VL. Impact of visceral....pdf: 1105142 bytes, checksum: bbbaf0c963858cd545018a3daf83495d (MD5)Made available in DSpace on 2016-04-12T13:12:51Z (GMT). No. of bitstreams: 1 Lanchote, VL. Impact of visceral....pdf: 1105142 bytes, checksum: bbbaf0c963858cd545018a3daf83495d (MD5) Previous issue date: 2015Faculdade de Ciências Farmacêuticas de Ribeirão Preto. Laboratório de Farmacocinética e Metabolismo. Departamento de Análises Clínicas, Toxicológicas e Bromatológicas. Ribeirão Preto, SP, BrasilUniversidade Federal de Sergipe. Hospital Universitário. Aracaju, SE, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, BrasilFaculdade de Ciências Farmacêuticas de Ribeirão Preto. Laboratório de Farmacocinética e Metabolismo. Departamento de Análises Clínicas, Toxicológicas e Bromatológicas. Ribeirão Preto, SP, BrasilFaculdade de Ciências Farmacêuticas de Ribeirão Preto. Laboratório de Farmacocinética e Metabolismo. Departamento de Análises Clínicas, Toxicológicas e Bromatológicas. Ribeirão Preto, SP, BrasilUniversidade Federal de Sergipe. Hospital Universitário. Aracaju, SE, BrasilUniversidade Federal de Sergipe. Hospital Universitário. Aracaju, SE, BrasilInstituto Nacional de Câncer. Divisão de Farmacologia. Rio de Janeiro, RJ, BrasilAIMS: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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