Chiral recognition of doxazosin enantiomers in 3 targets for therapy as well as adverse drug reactions in animal experiments

Abstract

Doxazosin used in benign prostatic hyperplasia has the side effects of causing hypotension and the risk of heart failure. The 3 targets of α(1A)-adrenoceptors (in the prostate), α(1D)-adrenoceptors (in the aorta), and an unknown mechanism (in the heart) are involved, respectively. We hypothesized that there is a chiral recognition of doxazosin enantiomers in the 3 targets. Using isolated rat aorta (α(1D)-adrenoceptors) and rabbit prostate (α(1A)-adrenoceptors), we examined pA(2) and pK(B) values of doxazosin enantiomers. We observed chronotropic and inotropic effects of doxazosin enantiomers in isolated rat and rabbit heart tissues. (-)Doxazosin and (+)doxazosin produced a shift to the right of concentration-contraction curves for noradrenalin (aorta) and phenylephrine (prostate smooth muscle). The pA(2) value of (-)doxazosin (8.625 ± 0.053) was smaller than (+)doxazosin (9.503 ± 0.051) in rat aorta, but their pK(B) values in rabbit prostate were the same. In rat and rabbit heart tissues, (+)doxazosin (3-30 µmol·L(-1)) significantly decreased atrial rate, and produced negative inotropic effects; however, (-)doxazosin did not affect the atrial rate, and produced positive inotropic effects in the atria. Thus, the chiral carbon atom of doxazosin does not affect its activity at the therapeutic target of α(1A)-adrenoceptors in the prostate, but significantly changes its blocking activity against α(1D)-adrenoceptors in the aorta, and produces opposite inotropic effects in the atria via an α(1)-adrenoceptor-independent mechanism.

(−)Doxazosin is a necessary component for the hypotensive effect of (±)doxazosin during long-term administration in conscious rats

“…The pK B value of (±)doxazosin treatment (8.694±0.032) was significantly smaller than that of (+)doxazosin treatment (8.995±0.032), but significantly larger than that of (-)doxazosin treatment (8.032±0.039). Previous studies also obtained similar results when observing the potency of (-)doxazosin, (+)doxazosin, and (±)doxazosin against NA-induced vasoconstriction via α 1 -adrenoceptors in the isolated rat thoracic aorta [11] and mesenteric artery [23] .…”

“…We further reported that (-)doxazosin, (+)doxazosin and (±)doxazosin treatment antagonized noradrenaline (NA)-induced vasoconstriction via α 1 -adrenoceptors in a competitive manner in the rat thoracic aortic ring preparation, and the pA 2 value for (-)doxazosin treatment was markedly less than those for (+)doxazosin and (±)doxazosin [11] . Similar results were confirmed in the isolated common carotid, ear, mesenteric, pulmonary arteries and the thoracic aorta of rabbits [12,13] .…”

Enantioselective Pharmacokinetics of Doxazosin and Pharmacokinetic Interaction Between the Isomers in Rats

“…8 The chiral carbon atom in the molecular structure of doxazosin does not affect the therapeutic activity at α 1A -adrenoceptors in the rabbit prostate, but it significantly affects the blocking activity at α 1Dadrenoceptors in the rat aorta. [9][10][11] Moreover, in rat and rabbit heart tissues, (+)-(S)-doxazosin significantly decreases the atrial rate and produces negative inotropic effects; however, (-)-(R)-doxazosin produces positive inotropic effects in the atria via an α 1 -adrenoceptor-independent mechanism. 9 In addition, Liu et al reported that the plasma concentration of (+)-(S)-doxazosin for all the timepoints tested was higher than that of (-)-(R)-doxazosin, and the area under the curve (AUC) of (+)-(S)-doxazosin was 2.3 times higher than that of (-)-(R)-doxazosin after oral administration of therapeutic doses of racemic doxazosin in two healthy volunteers.…”

“…[4][5][6][7] Doxazosin contains a chiral carbon at the 2-position of the 1, 4-benzodioxan-2-ylcarbonyl ring, consisting of two optical isomers, (+)-(S)-doxazosin and (-)-(R)-doxazosin, and it is used clinically as a racemate. [9][10][11] Moreover, in rat and rabbit heart tissues, (+)-(S)-doxazosin significantly decreases the atrial rate and produces negative inotropic effects; however, (-)-(R)-doxazosin produces positive inotropic effects in the atria via an α 1 -adrenoceptor-independent mechanism. (-)-(R)-doxazosin was shown to decrease the carotid blood pressure more weakly than (+)-(S)doxazosin in anesthetized rats.…”

“…The (+)-(S)-doxazosin and (-)-(R)-doxazosin do not have the same biological activity. 9 In addition, Liu et al reported that the plasma concentration of (+)-(S)-doxazosin for all the timepoints tested was higher than that of (-)-(R)-doxazosin, and the area under the curve (AUC) of (+)-(S)-doxazosin was 2.3 times higher than that of (-)-(R)-doxazosin after oral administration of therapeutic doses of racemic doxazosin in two healthy volunteers. 8 The chiral carbon atom in the molecular structure of doxazosin does not affect the therapeutic activity at α 1A -adrenoceptors in the rabbit prostate, but it significantly affects the blocking activity at α 1Dadrenoceptors in the rat aorta.…”