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Impact of visceral leishmaniasis and curative chemotherapy on cytochrome P450 activity in Brazilian patients
Author(s) -
Lanchote Vera Lucia,
Almeida Roque,
Barral Aldina,
BarralNetto Manoel,
Marques Maria Paula,
Moraes Natália V.,
Silva Angela M.,
Souza Tania M. V.,
SuarezKurtz Guilherme
Publication year - 2015
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12677
Subject(s) - cyp3a , cyp2c19 , omeprazole , losartan , medicine , cyp2c9 , pharmacology , gastroenterology , cyp3a4 , chemotherapy , pharmacokinetics , midazolam , cytochrome p450 , angiotensin ii , receptor , metabolism , sedation
Aims 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.