Enantiomeric analysis of the five major monohydroxylated metabolites of methaqualone in human urine by chiral capillary electrophoresis.
Methaqualone (MQ; 2-methyl-3-o-tolylquinazolin-4(3H)-one) is a hypnotic and anticonvulsive drug in which the rotation about the nitrogen-to-aryl bond between the planar 2-methyl-quinazolin-4(3H)-one structure and the o-tolyl moiety is sterically hindered at body temperature. MQ and its five major monohydroxylated metabolites found in urine, 4'-hydroxymethaqualone (4'OH-MQ), 2'-hydroxymethaqualone (2'-OH-MQ), 3'-hydroxymethaqualone (3'OH-MQ), 2-hydroxymethaqualone (2OH-MQ) and 6-hydroxymethaqualone (6OH-MQ), are thus chiral substances whose enantiomers are shown to be separable by chiral capillary electrophoresis at pH 2.1 in the presence of 50 mM (2-hydroxypropyl)-beta-cyclodextrin (OHP-beta-CD). Other neutral derivatives of beta-CD, namely (2-hydroxypropyl)-gamma-CD, (2,3,6-trimethyl)-beta-CD, and (2,6-di-O-methyl)-beta-CD were found to be able to resolve the enantiomers of some but not all of these six components. With OHP-beta-CD, simultaneous analysis of the enantiomers of MQ and its five metabolites is hampered by the difficulty in separating MQ and 4'OH-MQ, the major urinary metabolite. A two-step solid phase extraction process is shown to permit discrimination between these two compounds and thus analysis of MQ enantiomers in unhydrolyzed urines that were collected overnight after administration of 250 mg of racemic MQ. Furthermore, analysis of liquid/liquid or solid-phase extracts of enzymatically hydrolyzed urines reveals the distribution of the enantiomers of the five hydroxymetabolites of MQ and, for the first time, insight into the stereoselectivity of the MQ metabolism. The major metabolite, 4'OH-MQ, is shown to be excreted almost exclusively as single enantiomer. The two urinary enantiomers of 6OH-MQ are present at about equal amounts, whereas unequal amounts are noted for the enantiomers of 3'OH-MQ, 2OH-MQ, and 2'OH-MQ.
Prost
F
F
Department of Clinical Pharmacology, University of Bern, Switzerland.
Thormann
W
W
D003505:Cyclodextrins / Q000737:chemistry; D019075:Electrophoresis, Capillary / Q000379:methods*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006900:Hydroxylation; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000378:metabolism / Q000652:urine*; D009682:Magnetic Resonance Spectroscopy; D008702:Methaqualone / Q000008:administration & dosage / Q000378:metabolism / Q000652:urine*; D013237:Stereoisomerism; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D006993:Hypnotics and Sedatives; D047392:beta-Cyclodextrins; D008702:Methaqualone; C031215:betadex