title: Development and validation of an improved HPLC-MS/MS method for comparative pharmacokinetics of penehyclidine hydrochloride following a single intravenous or intramuscular injection.
abstract: Penehyclidine hydrochloride (PHC) is an anticholinergic drug with both antimuscarinic and antinicotinic activity. In order to compare the pharmacokinetics of two administration routes (intravenous injection (i.v.) and intramuscular injection (i.m.)) of PHC, an improved High Performance Liquid Chromatography Tandem Mass Spectrometry (HPLC-MS/MS) bioanalytical method was developed for the quantification of PHC in plasma and urine using verapamil as the internal standard (I.S.). Chromatography was performed using a Thermo Hypersil GOLD column (30mm×2.1mm, 3μm), with a gradient elution of 1‰ formic acid-10mmol/L ammonium acetate and acetonitrile at 0.3mL/min. Detection and quantitation were performed by electrospray ionization (ESI) and multiple reaction monitoring (MRM) in the positive ion mode. The most intense [M+H](+) MRM transition of PHC at m/z 316.2→128.3 was used for PHC quantitation, and the transition at m/z 454.6→303.2 was used to monitor I.S. The lower limit of quantification (LLOQ) was 0.05 ng/mL. The intraday precision was <6.71% and the interday precision was <11.69%. The pharmacokinetic parameters of i.v. and i.m. administration routes were as follows (i.v. vs i.m.): t1/2 15.73 vs 17.24h, Tmax 0.06 vs 0.26h, AUC0-t 69.35 vs 67.90hng/mL, AUC0-inf 78.24 vs 79.67hng/mL, Cmax 37.5 vs 9.1ng/mL, Ae0-24h 22.7 vs 25.21μg. There were no significant differences between parameters t1/2 and AUC (P>0.05), but significant differences were observed in Cmax, Tmax and Ae0-24h between the two administration routes (P<0.05). The mean absolute bioavailability of the i.m. administration route was 98.4% (95% confidence interval, 93.4-103.6%). Safety results showed that PHC appeared to be well tolerated in both i.v. and i.m. administration routes and pharmacokinetic results showed that PHC was nearly completely absorbed via i.m. administration route.
authors.affiliation: Department of Pharmacy, Peking University People's Hospital, Beijing 100044, China.
authors.forename: Libo
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Pharmacy, Peking University People's Hospital, Beijing 100044, China; Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yannan
authors.initials: Y
authors.lastname: Zang
authors.affiliation: Department of Pharmacy, Peking University People's Hospital, Beijing 100044, China.
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pharmacy, Peking University People's Hospital, Beijing 100044, China.
authors.forename: Zhongna
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Department of Pharmacy, Peking University People's Hospital, Beijing 100044, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Jing
authors.affiliation: Department of Pharmacy, Peking University People's Hospital, Beijing 100044, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Critical Care Medicine, Peking University People's Hospital, Beijing 100044, China.
authors.forename: Youzhong
authors.initials: Y
authors.lastname: An
authors.affiliation: Department of Pharmacy, Peking University People's Hospital, Beijing 100044, China. Electronic address: fangyipkuph@163.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of Pharmacy, Peking University People's Hospital, Beijing 100044, China. Electronic address: phaseistudy@163.com.
authors.forename: Wanyu
authors.initials: W
authors.lastname: Feng
mesh_terms: D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D057230:Limit of Detection; D008297:Male; D011812:Quinuclidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D012015:Reference Standards; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D011812:Quinuclidines; C486140:penehyclidine
keywords: Bioavailability; Comparative pharmacokinetics; Intramuscular injection (i.m.); Intravenous injection (i.v.); Penehyclidine hydrochloride (PHC)