Biotransformation of prochiral 2-phenyl-1,3-di(4-pyridyl)-2-propanol to a chiral N-oxide metabolite.
The prochiral compound, 2-phenyl-1,3-di(4-pyridyl)-2-propanol (PPP) labeled with 3H in the phenyl ring, was administered to rats, dogs, and a human subject. Paper chromatography of the urine indicated that a major metabolite common to all three species was excreted. This metabolite was isolated from the urine of chronically dosed dogs and was identified by mass, nuclear magnetic resonance (NMR), and infrared spectrometry as the N-oxide, 2-phenyl-1-(4-pyridyl)-3-(4-pyridyl-1-oxide)-2-propanol. In addition, polarimetry indicated that this metabolite was levorotatory. Examination of the enantiomeric purity of a crystallized sample of the metabolite by NMR spectroscopy of resolvable diastereomeric salts formed with lasalocid revealed the presence of only the levorotatory enantiomer. Accordingly, this metabolic N-oxide formation in the dog was at least stereoselective, and perhaps stereospecific. The N-oxidation of PPP was also demonstrated in vitro with 9000 g supernatant fraction of rat liver fortified with an NADPH generating system, and this reaction was inducible by phenobarbital, indicating that it is mediated by the cytochrome P-450 mixed-function oxidase system. This study, in addition to providing another example of the pyridyl N-oxidation pathway, illustrates the necessity of considering the stereochemical aspects of the metabolism of prochiral drugs.
D000433:1-Propanol / Q000378:metabolism; D000328:Adult; D000818:Animals; D001711:Biotransformation; D003497:Cyclic N-Oxides / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010084:Oxidation-Reduction; D020005:Propanols; D011725:Pyridines / Q000378:metabolism*; D051381:Rats; D013237:Stereoisomerism; D013997:Time Factors
D003497:Cyclic N-Oxides; D020005:Propanols; D011725:Pyridines; C018633:2-phenyl-1,3-di(4-pyridyl)-2-propanol; C018636:2-phenyl-1-(4-pyridyl)-3-(4-pyridyl-1-oxide)-2-propanol; D000433:1-Propanol