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


CONCLUSIONS
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.
Laboratório de Farmacocinética e Metabolismo, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Ribeirão Preto, São Paulo, Brazil.
Vera Lucia
VL
Lanchote
Universidade Federal de Sergipe, Hospital Universitário, Aracaju, Sergipe, Brazil.
Roque
R
Almeida
Centro de Pesquisas Gonçalo Moniz (CPqGM), Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil.
Aldina
A
Barral
Centro de Pesquisas Gonçalo Moniz (CPqGM), Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil.
Manoel
M
Barral-Netto
Laboratório de Farmacocinética e Metabolismo, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Ribeirão Preto, São Paulo, Brazil.
Maria Paula
MP
Marques
Laboratório de Farmacocinética e Metabolismo, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Ribeirão Preto, São Paulo, Brazil.
Natália V
NV
Moraes
Universidade Federal de Sergipe, Hospital Universitário, Aracaju, Sergipe, Brazil.
Angela M
AM
da Silva
Universidade Federal de Sergipe, Hospital Universitário, Aracaju, Sergipe, Brazil.
Tania M V
TM
Souza
Divisão de Farmacologia, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
Guilherme
G
Suarez-Kurtz
D000293:Adolescent; D000328:Adult; D001938:Brazil; D065731:Cytochrome P-450 CYP2C19 / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006801:Humans; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000201:enzymology*; D019808:Losartan / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D009853:Omeprazole / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
D003577:Cytochrome P-450 Enzyme System; D065729:Cytochrome P-450 CYP2C9; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D019808:Losartan; D009853:Omeprazole; D008874:Midazolam
Brazil; CYP2C19; CYP2C9; CYP3A4; IL-6; visceral leishmaniasis