TITLE

Simultaneous HPLC Determination of Metronidazole and Spiramycin in Plasma and Brain of Mouse

AUTHOR(S)
Kit, Chew W.; Segarra, Ignacio
PUB. DATE
November 2011
SOURCE
Current Pharmaceutical Analysis;Nov2011, Vol. 7 Issue 4, p262
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Treatments fail to eliminate Toxoplasma gondii due to low drug brain penetration. Spiramycin is an Mrp2, P-glycoprotein substrate, active in acute and chronic murine toxoplasmosis. Metronidazole is a CYP3A4 inhibitor and P-glycoprotein substrate. We developed a simple HPLC method to analyze spiramycin and metronidazole simultaneously. Male Balb/c mice were randomly selected in three groups and were dosed orally either 500 mg/kg metronidazole (group 1, n=4) or 400 mg/kg spiramycin (group 2, n=4) or coadministered 500 mg/kg metronidazole 30 min prior to 400 mg/kg spiramycin (group 3, n=4). Mice were euthanized 2 hours after spiramycin administration. Metronidazole and spiramycin brain and plasma concentrations were measured by HPLC using a Phenomenex� C-18 (150x3.8 mm, 5 �m) column and acetonitrile-phosphate buffer (pH 2.5) gradient elution (20/80 to 30/70 in 3 min) at 1 mL/min flow, 29�C and 232 nm. The method was linear (0.25-50.0 �g/mL), the LLOQ was 0.25 �g/mL, intra- and interday variability, precision and accuracy were within 15%. Recoveries were above 75% and there was no matrix interference. Metronidazole eluted at 3 min and spiramycin at 5 min. Spiramycin did not affect plasma metronidazole concentration (6.93�0.48 �g/mL in combination vs. alone 7.65�0.55 �g/mL) or brain (2.96�0.60 �g/g after coadministration vs. control, 4.02�0.78 �g/g). Metronidazole did not change spiramycin plasma concentration (coadministration: 3.94�1.30 �g/mL, control: 3.71�0.94 �g/mL). However, spiramycin brain concentration increased 2-fold after metronidazole coadministration from 2.44�0.33 �g/g to 4.83�1.25 �g/g (P < 0.05). Metronidazole increased spiramycin brain uptake, probably due to P-glycoprotein inhibition, which may improve toxoplasmosis encephalitis treatments.
ACCESSION #
70064412

 

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