title: Poor and enantioselective bioavailability of naftopidil enantiomers is due to extensive and stereoselective metabolism in rat liver.
abstract: Racemic naftopidil (NAF) is used to treat benign prostatic hyperplasia (BPH) and prostatic cancer (PCa). It exhibits greater efficacy but requires higher dose than other ɑ1-adrenoceptor blockers because of its poor bioavailability. It was previously shown that bioavailability of S(-)-NAF (14.5%) was twice that of R(+)-NAF (6.8%). The present study aimed to elucidate the major factors contributing to the poor and enantioselective bioavailability of NAF. First, absorption of NAF enantiomers was examined using a perfusated intestinal model. NAF enantiomers were found to be equally and highly permeable in all segments of the intestine. Second, the metabolites formed in different parts of the intestine and in bile were investigated. Glucuronidation of NAF enantiomers was found to occur primarily in the liver. Third, a new method consisting of ultra performance liquid chromatography coupled with triple-quadruple mass spectrometry (UPLC-MS/MS) was employed to quantify and calculate the pharmacokinetic parameters of NAF enantiomers and their glucuronides after the enantiomers were intravenously injected into rats. The amounts of R(+)-NAF glucuronide (R(+)-NAF-G) and S(-)-NAF glucuronide (S(-)-NAF-G) were six-fold higher than that of R(+)-NAF, and three-fold higher than that of S(-)-NAF. Glucuronidation of S(-)-NAF was faster than that of R(+)-NAF, but the conjugated amount was half of that of R(+)-NAF. Thus, bioavailability of S(-)-NAF was twice that of R(+)-NAF. In conclusion, extensive phase II metabolism in the liver significantly contributes to the low bioavailability of NAF enantiomers. Glucuronidation is the most important metabolic pathway for NAF enantiomers. Glucuronidation of S(-)-NAF is faster but occurs to a lesser extent than that of R(+)-NAF.
authors.affiliation: College of Pharmacy, Guangzhou Medical University, Guangzhou 511436, PR China. Electronic address: melody_12@163.com.
authors.forename: Xiawen
authors.initials: X
authors.lastname: Liu
authors.affiliation: International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhu
authors.affiliation: College of Pharmacy, Guangzhou Medical University, Guangzhou 511436, PR China.
authors.forename: Biyun
authors.initials: B
authors.lastname: Huang
authors.affiliation: College of Pharmacy, Guangzhou Medical University, Guangzhou 511436, PR China.
authors.forename: Junjun
authors.initials: J
authors.lastname: Huang
authors.affiliation: College of Pharmacy, Guangzhou Medical University, Guangzhou 511436, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cai
authors.affiliation: College of Pharmacy, Guangzhou Medical University, Guangzhou 511436, PR China.
authors.forename: Liu
authors.initials: L
authors.lastname: Zhu
authors.affiliation: College of Pharmacy, Guangzhou Medical University, Guangzhou 511436, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wu
authors.affiliation: College of Pharmacy, Guangzhou Medical University, Guangzhou 511436, PR China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Fu
authors.affiliation: College of Pharmacy, Guangzhou Medical University, Guangzhou 511436, PR China.
authors.forename: Xingfei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: College of Pharmacy, Guangzhou Medical University, Guangzhou 511436, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Rong
authors.affiliation: College of Pharmacy, Guangzhou Medical University, Guangzhou 511436, PR China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Guangzhou Hospital of Traditional Chinese Medicine, Guangzhou 510130, PR China.
authors.forename: Jiewen
authors.initials: J
authors.lastname: Guo
authors.affiliation: Guangzhou Hospital of Traditional Chinese Medicine, Guangzhou 510130, PR China.
authors.forename: Arong
authors.initials: A
authors.lastname: Li
authors.affiliation: Department of Endocrinology, Taihe Hospital (Hubei University of Medicine), Shiyan, Hubei 442000, PR China.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Guo
authors.affiliation: College of Pharmacy, Guangzhou Medical University, Guangzhou 511436, PR China. Electronic address: mryuanmu838@sina.com.
authors.forename: Mu
authors.initials: M
authors.lastname: Yuan
mesh_terms: D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D007262:Infusions, Intravenous; D007422:Intestines / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism* / Q000493:pharmacokinetics*; D010879:Piperazines / Q000378:metabolism* / Q000493:pharmacokinetics*; D011470:Prostatic Hyperplasia / Q000188:drug therapy; D011786:Quality Control; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry; D013696:Temperature
chemical_list: D020719:Glucuronides; D009281:Naphthalenes; D010879:Piperazines; C064357:naftopidil
keywords: Glucuronidation; Intestinal absorption; Naftopidil enantiomers; Pharmacokinetics; UPLC–MS/MS