Identification and quantitative determination of benproperine metabolites in human plasma and urine by liquid chromatography-tandem mass spectrometry.
Two novel metabolites of benproperine (BPP), 1-[1-methyl-2-[2-(phenylmethyl)phenoxy]ethyl]-3-piperidinol (3-OH-BPP) and 1-[1-methyl-2-[2-(phenylmethyl)phenoxy]ethyl]-4-piperidinol (4-OH-BPP), were confirmed by comparison of retention times and mass spectra with those of synthetic standards using liquid chromatography-tandem mass spectrometry. Selective and sensitive procedures were developed for the simultaneous determination of BPP, 3-OH-BPP and 4-OH-BPP in human plasma and urine. The analytes were extracted from plasma sample and enzymatically hydrolyzed urine samples by liquid-liquid extraction, separated through a Diamonsil C(18) column (150 mm x 4.6 mm i.d.) and determined by tandem mass spectrometry with an electrospray ionization interface in selected reaction monitoring mode. Dextromethorphan was used as internal standard. The mobile phase consisted of acetonitrile-water-formic acid (34:66:1, v/v/v), and flow-rate was 0.5 ml min(-1). This method has a lower limit of quantification (LLOQ) of 60, 4.0 and 4.0 nmol l(-1)for BPP, 3-OH-BPP and 4-OH-BPP in plasma, 4.9, 4.7 and 2.4 nmol l(-1) in urine, respectively. The intra- and inter-run precision were measured to be below 9.2%, and the accuracy was within +/-4.3% for the analytes. The method was successfully used to determine BPP, 3-OH-BPP and 4-OH-BPP in plasma and urine for pharmacokinetic investigation. The results indicated residue of 3-OH-BPP in the body at least 192 h after an oral dose of BPP.
Li
Yan
Y
Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University, Shenyang, PR China.
Sun
Yuming
Y
Dong
Yu
Y
Zhang
Yifan
Y
Zhong
Dafang
D
D000996:Antitussive Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000652:urine*; D001559:Benzhydryl Compounds / Q000097:blood* / Q000493:pharmacokinetics / Q000652:urine*; D002138:Calibration; D002853:Chromatography, Liquid / Q000379:methods*; D006801:Humans; D010880:Piperidines / Q000097:blood* / Q000493:pharmacokinetics / Q000652:urine*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*
D000996:Antitussive Agents; D001559:Benzhydryl Compounds; D010880:Piperidines; C477447:benproperine