Microbial production of phase I and phase II metabolites of midazolam.
Midazolam, a potent benzodiazepine derivative and a typical substrate of CYP3A4/3A5, is essentially metabolized in human into 1'-hydroxymidazolam, then eliminated as the corresponding phase II metabolite, the 1'-O-β-D-glucuronide derivative. A high yield alternative to the current multistep synthesis of 1'-hydroxymidazolam is described, using a biotransformation of midazolam by a fungal microorganism, Beauveria bassiana. The corresponding phase II metabolite, 1'-hydroxymidazolam-1'-O-β-D-glucuronide, has been then prepared by chemical synthesis (3 steps, 20% yield), or by microbial glucuronidation (one step, 20% yield) using a Streptomyces sp. strain. The use of the same Streptomyces strain allows a direct and expeditive synthesis of the same glucuronide conjugate from midazolam itself in an advantageous 17% yield.
Bertin Pharma, Parc d'Activités du Pas du Lac, Montigny-le-Bretonneux, France. robert.azerad@parisdescartes.fr
Cyrille
C
Marvalin
Mireille
M
Denoux
Serge
S
Pérard
Sébastien
S
Roy
Robert
R
Azerad
D052982:Beauveria / Q000187:drug effects / Q000378:metabolism*; D001711:Biotransformation / Q000187:drug effects; D002853:Chromatography, Liquid; D004952:Esters / Q000737:chemistry / Q000378:metabolism; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D050216:Metabolic Detoxication, Phase I; D050217:Metabolic Detoxication, Phase II; D008874:Midazolam / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013302:Streptomyces / Q000187:drug effects / Q000378:metabolism*
D004952:Esters; D020719:Glucuronides; C040081:1-hydroxymethylmidazolam; D008874:Midazolam