title: The truth about the lower plasma concentration of the (-)-isomer after racemic doxazosin administration in rats: Stereoselective inhibition of the (-)-isomer by the (+)-isomer at CYP3A.
abstract: Doxazosin (DOX), a long-lasting α1-adrenoceptor antagonist, is used clinically as a racemate that consists of two optical isomers. In humans and rats, following oral administration of racemic DOX [(±)-DOX], the plasma concentration of the (-)-isomer is lower than that of the (+)-isomer, but the mechanism for this interaction is not known. In this study, a chiral HPLC with fluorescence detection was used to measure the drug concentrations for analysis of the stereoselective metabolism of DOX in in vivo and in vitro experiments. We found that the plasma levels of the (-)-isomer were significantly lower than those of the (+)-enantiomer following i.v. administration of (±)-DOX to the rats and that the depletion rate constant (kdep) of (-)-DOX (0.0107±0.0007L/min) was significantly larger than that of (+)-DOX (kdep 0.0088±0.0005L/min) (p<0.05) when (±)-DOX was incubated with rat liver microsomes (RLMs). However, (-)-DOX was not depleted faster than (+)-DOX following their separate incubation with RLMs. The metabolism of (-)- or (+)-isomer in RLMs was catalysed by CYP3A because the depletion of the compounds was inhibited by ketoconazole (a potent CYP3A-selective inhibitor) similarly. More importantly, the kdep of (+)-DOX in the 1.0/2.0 and 0.5/2.5 (+)-DOX/(-)-DOX mixtures was significantly lower than that of (-)-DOX in the 1.0/2.0 and 0.5/2.5 (-)-DOX/(+)-DOX mixtures (p<0.05). In conclusion, although (-)-DOX is not depleted faster than (+)-DOX when only a single isomer of DOX is incubated with rat liver microsomes, it is depleted much faster than (+)-DOX when a mixture of the two isomers was used, suggesting a prominent and stereoselective inhibition of the (-)-isomer over the (+)-isomer at the CYP3A enzyme.
authors.affiliation: School of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang, China.
authors.forename: Dezhi
authors.initials: D
authors.lastname: Kong
authors.affiliation: School of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: School of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang, China.
authors.forename: Panpan
authors.initials: P
authors.lastname: Zhang
authors.affiliation: School of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: School of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang, China.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Zhen
authors.affiliation: School of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang, China. Electronic address: ren-leiming@263.net.
authors.forename: Leiming
authors.initials: L
authors.lastname: Ren
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D017292:Doxazosin / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D051381:Rats; D013050:Spectrometry, Fluorescence; D013237:Stereoisomerism
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D051544:Cytochrome P-450 CYP3A; D017292:Doxazosin
keywords: 4-Methylpyrazole (PubChem CID: 3406); CYPs; Chemical inhibition; Doxazosin (PubChem CID: 3157); Doxazosin enantiomers; Enantiomer–enantiomer interaction; Ketoconazole (PubChem CID: 3823); Prazosin (PubChem CID: 4893); Quinidine (PubChem CID: 1065); R-doxazosin (PubChem CID: 6604102); Rat liver microsomes; Stereoselective pharmacokinetics; Sulfamethoxazole (PubChem CID: 5329); α-Naphthoflavone (PubChem CID: 11790)