Enantioselective distribution of albendazole metabolites in cerebrospinal fluid of patients with neurocysticercosis.
OBJECTIVE
Albendazole (ABZ) is effective in the treatment of neurocysticercosis. ABZ undergoes extensive metabolism to (+) and (-)-albendazole sulphoxide (ASOX), which are further metabolized to albendazole sulphone (ASON). We have investigated the distribution of (+)-ASOX (-)-ASOX, and ASON in cerebrospinal fluid (CSF) of patients with neurocysticercosis.


METHODS
Twelve patients with a diagnosis of active brain parenchymal neurocysticercosis treated with albendazole for 8 days (15 mg kg(-1) day(-1)) were investigated. On day 8, serial blood samples were collected during the dose interval (0-12 h) and one CSF sample was taken from each patient by lumbar puncture at different time points up to 12 h after the last albendazole dose. Albendazole metabolites were determined in CSF and plasma samples by h.p.l.c. using a Chiralpak AD column and fluorescence detection. Population curves for CSF albendazole metabolite concentration vs time were constructed.


RESULTS
The mean plasma/CSF ratios were 2.6 (95% CI: 1.9, 3.3) for (+)-ASOX and 2.7 (95% CI: 1.8, 3.7) for (-)-ASOX, with the two-tailed P value of 0.9873 being non-significant. These data indicate that the transport of ASOX through the blood-brain barrier is not enantioselective, but rather depends on passive diffusion. The present results suggest the accumulation of the (+)-ASOX metabolite in the CSF of patients with neurocysticercosis. The CSF AUC(+)/AUC(-) ratio was 3.4 for patients receiving albendazole every 12 h. The elimination half-life of both ASOX enantiomers in CSF was 2.5 h. ASOX was the predominant metabolite in the CSF compared with ASON; the CSF AUC(ASOX)/AUC(ASON) ratio was approximately 20 and the elimination half-life of ASON in CSF was 2.6 h.


CONCLUSIONS
We have demonstrated accumulation of the (+)-ASOX metabolite in CSF, which was about three times greater than the (-) antipode. ASOX concentrations were approximately 20 times higher than those observed for the ASON metabolite.
Faculdade de Medicina de Ribeirão Preto, USP, Ribeirão Preto, Brazil.
O M
OM
Takayanagui
P S
PS
Bonato
S A C
SA
Dreossi
V L
VL
Lanchote
D000328:Adult; D015766:Albendazole / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000871:Anthelmintics / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001927:Brain Diseases / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020019:Neurocysticercosis / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000378:metabolism; D013237:Stereoisomerism
D000871:Anthelmintics; C027187:albendazole sulfone; D015766:Albendazole; C027186:albendazole sulfoxide