Cytochrome P450 (CYP)
enzymes are involved in the
biotransformation of
chloroquine (CQ), but the
role of the different profiles of
metabolism of this
drug in relation to
Plasmodium vivax recurrences has not been properly investigated. To investigate the influence of the CYP
genotypes associated with CQ
metabolism on the rates of P. vivax early
recurrences, a
case-control study was carried out. The cases included
patients presenting with an early
recurrence (CQ-recurrent individuals), defined as a
recurrence during the first 28 days after initial
infection and
plasma concentrations of CQ plus desethylchloroquine (DCQ; the major CQ metabolite) higher than 100 ng/ml. A
control group with no
parasite recurrence over the follow-up (the CQ-responsive group) was also included. CQ and DCQ
plasma levels were measured on day 28. CQ-metabolizing CYP (
CYP2C8,
CYP3A4, and
CYP3A5)
genotypes were determined by
real-time PCR. An ex vivo study was conducted to verify the
efficacy of CQ and DCQ against P. vivax isolates. The frequency of
alleles associated with normal and slow
metabolism was
similar between the cases and the controls for the
CYP2C8 (
odds ratio [OR] = 1.45, 95%
confidence interval [CI] = 0.51 to 4.14, P = 0.570),
CYP3A4 (OR = 2.38, 95% CI = 0.92 to 6.19, P = 0.105), and
CYP3A5 (OR = 4.17, 95% CI = 0.79 to 22.04, P = 1.038)
genes. DCQ levels were higher than CQ levels, regardless of the
genotype. Regarding the DCQ/CQ ratio, there was no difference between groups or between those
patients who had a normal
genotype and those
patients who had a mutant
genotype. DCQ and CQ showed
similar efficacy ex vivo CYP
genotypes had no influence on early
recurrence rates. The
similar efficacy of CQ and DCQ ex vivo could explain the absence of
therapeutic failure, despite the presence of
alleles associated with slow
metabolism.