Enantioselective Pharmacokinetics of Doxazosin and Pharmacokinetic Interaction Between the Isomers in Rats. Issue 10 (23rd July 2015)

• Record Type: Journal Article
• Authors: Li, Qing; Kong, Dezhi; Du, Qian; Zhao, Jing; Zhen, Yaqin; Li, Tonghui; Ren, Leiming
• Is Part Of: Chirality. Volume 27:Issue 10(2015)
• Page Start: 738
• Page End: 744
• Publication Date: 2015-07-23
• Subjects: Chirality -- Periodicals; Pharmaceutical chemistry -- Periodicals; 541.22
• DOI: 10.1002/chir.22483
• Languages: English
• ISSNs: 0899-0042

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <p>In this study, the <named-content content-type="reactionType" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">stereoselective</named-content> pharmacokinetics of doxazosin enantiomers and their pharmacokinetic interaction were studied in rats. Enantiomer concentrations in plasma were measured using chiral high‐pressure <named-content content-type="chemicalTechnology" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">liquid chromatography</named-content> (HPLC) with fluorescence detection after oral or intravenous administration of (–)‐(R)‐doxazosin 3.0 mg/kg, (+)‐(S)‐doxazosin 3.0 mg/kg, and rac‐doxazosin 6.0 mg/kg. AUC values of (+)‐(S)‐doxazosin were always larger than those of (–)‐(R)‐doxazosin, regardless of oral or intravenous administration. The maximum plasma concentration (<italic>C<sub>max</sub></italic>) value of (–)‐(R)‐doxazosin after oral administration was significantly higher when given alone (110.5 ± 46.4 ng/mL) versus in racemate (53.2 ± 19.7 ng/mL), whereas the <italic>C<sub>max</sub></italic> value of (+)‐(S)‐doxazosin did not change significantly. The area under the curve (AUC) and <italic>C<sub>max</sub></italic> values for (+)‐(S)‐doxazosin after intravenous administration were significantly lower, and its <italic>Cl</italic> value significantly higher, when given alone versus in racemate. We speculate that (–)‐(R)‐doxazosin increases (+)‐(S)‐doxazosin exposure probably by inhibiting the elimination of (+)‐(S)‐doxazosin, and the enantiomers may be competitively absorbed from the gastrointestinal tract. In conclusion, doxazosin pharmacokinetics are substantially stereospecific and enantiomer–enantiomer interaction occurs after rac‐administration. <italic>Chirality 27:738–744, 2015</italic>. © 2015 Wiley Periodicals, Inc.</p> </abstract>