title: Metronidazole and hydroxymetronidazole central nervous system distribution: 1. microdialysis assessment of brain extracellular fluid concentrations in patients with acute brain injury.
abstract: The distribution of metronidazole in the central nervous system has only been described based on cerebrospinal fluid data. However, extracellular fluid (ECF) concentrations may better predict its antimicrobial effect and/or side effects. We sought to explore by microdialysis brain ECF metronidazole distribution in patients with acute brain injury. Four brain-injured patients monitored by cerebral microdialysis received 500 mg of metronidazole over 0.5 h every 8 h. Brain dialysates and blood samples were collected at steady state over 8 h. Probe recoveries were evaluated by in vivo retrodialysis in each patient for metronidazole. Metronidazole and OH-metronidazole were assayed by high-pressure liquid chromatography, and a noncompartmental pharmacokinetic analysis was performed. Probe recovery was equal to 78.8% ± 1.3% for metronidazole in patients. Unbound brain metronidazole concentration-time curves were delayed compared to unbound plasma concentration-time curves but with a mean metronidazole unbound brain/plasma AUC0-τ ratio equal to 102% ± 19% (ranging from 87 to 124%). The unbound plasma concentration-time profiles for OH-metronidazole were flat, with mean average steady-state concentrations equal to 4.0 ± 0.7 μg ml(-1). This microdialysis study describes the steady-state brain distribution of metronidazole in patients and confirms its extensive distribution.
authors.affiliation: Inserm U1070, Pole Biologie Santé, Poitiers, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Frasca
authors.forename: Claire
authors.initials: C
authors.lastname: Dahyot-Fizelier
authors.forename: Christophe
authors.initials: C
authors.lastname: Adier
authors.forename: Olivier
authors.initials: O
authors.lastname: Mimoz
authors.forename: Bertrand
authors.initials: B
authors.lastname: Debaene
authors.forename: William
authors.initials: W
authors.lastname: Couet
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchand
mesh_terms: D000368:Aged; D000890:Anti-Infective Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000097:blood* / Q000188:drug therapy / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D045604:Extracellular Fluid / Q000737:chemistry*; D006801:Humans; D008297:Male; D008795:Metronidazole / Q000378:metabolism / Q000493:pharmacokinetics*; D017551:Microdialysis; D008875:Middle Aged
chemical_list: D000890:Anti-Infective Agents; D008795:Metronidazole