Modeling of Relationships between Pharmacokinetics and Blockade of Agonist-Induced Elevation of Intraurethral Pressure and Mean Arterial Pressure in Conscious Dogs Treated with α₁-Adrenoceptor Antagonists

Abstract

Fiduxosin is a new ␣ 1 -adrenoceptor antagonist targeted for the treatment of symptomatic benign prostatic hyperplasia. The purpose of this study was to determine and compare the potencies of the ␣ 1 -adrenoceptor antagonists terazosin, doxazosin, tamsulosin, and fiduxosin, based on relationships between plasma drug concentrations and blockade of phenylephrine (PE)-induced intraurethral (IUP) and mean arterial pressure (MAP) responses after single oral dosing in conscious male beagle dogs. Magnitude of blockade and plasma concentrations were evaluated at selected time points over 24 h. All drugs produced dose-dependent antagonism of PE-induced IUP and MAP responses. When IUP and MAP blockade effects were plotted against drug plasma concentrations, direct relationships were observed that were well described by the sigmoidal maximal effect model. IUP IC 50 values for terazosin, doxazosin, tamsulosin, and fiduxosin were 48.6, 48.7, 0.42, and 261 ng/ml, respectively. MAP IC 50 values were 12.2, 13.8, 1.07, and 1904 ng/ml, respectively. Uroselectivity index values, defined as MAP IC 50 /IUP IC 50 , were 0.25, 0.28, 2.6, and 7.3, respectively. These results extend previous observations with terazosin in this model, showing that doxazosin exhibits a uroselectivity index comparable to terazosin, consistent with the lack of ␣ 1 -adrenoceptor subtype selectivity or uroselectivity of these drugs. Tamsulosin, an ␣ 1a -/␣ 1d -subtype selective agent, had an index value approximately 10-fold greater than the nonselective drugs. Based on its pharmacokinetic profile and a relative uroselectivity 29-fold greater than the nonselective drugs, fiduxosin is expected to exhibit greater selectivity for urethral compared with vascular ␣ 1 -adrenoceptors in human and should be a novel, long-acting, uroselective ␣ 1 -adrenoceptor antagonist.␣ 1 -Adrenoceptor antagonists represent first-line therapy for the pharmacological treatment of benign prostatic hyperplasia (BPH), in part by relaxing prostatic smooth muscle (Lowe, 1999). Fiduxosin (ABT-980) is a novel ␣ 1 -adrenoceptor antagonist. Compared with other clinical agents, such as terazosin, doxazosin, and tamsulosin, fiduxosin exhibits a somewhat different ␣ 1 -adrenoceptor subtype selectivity profile. Radioligand binding potencies at human ␣ 1a -, ␣ 1b -, and ␣ 1d -adrenoceptors are reported to be 1.81, 1.16, and 0.67 nM for terazosin; 0.79, 0.80, and 0.81 nM for doxazosin; 0.03, 0.60, and 0.06 nM for tamsulosin; and 0.16, 24.89, and 0.92 nM for fiduxosin, respectively (Hancock et al., 1998b(Hancock et al., , 2002, showing fiduxosin to be selective for ␣ 1a -and ␣ 1d -adrenoceptors compared with ␣ 1b -adrenoceptors to a greater extent than tamsulosin.Accumulating data suggest that extraprostatic ␣ 1 -adrenoceptors in bladder, spinal cord, ganglia, or nerve terminals may also contribute to ameliorating the irritative and voiding symptoms of BPH (Fitzpatrick, 2000;Schwinn and Michelotti, 2000). Three subtypes of ␣ 1 -adrenoceptors are known to exist, ␣ 1A -, ␣ 1B -, and ␣ 1D -adr...

Effect of Fiduxosin, an Antagonist Selective for α1A- and α1D-Adrenoceptors, on Intraurethral and Arterial Pressure Responses in Conscious Dogs

“…The enhanced relative selectivity shown herein of tamsulosin compared with terazosin is consistent with the selectivity rank order reported in other models Witte et al, 2002) and in clinical studies (Djavan and Marberger, 1999;Schafers et al, 1999). The in vitro and in vivo profile of fiduxosin is similar to that of another ␣ 1A -and ␣ 1D -selective antagonist, A-131701 (Hancock et al, 1998a,b).…”

“…5 where MAP blockade was less at equieffective doses of the antagonists that produce 75% inhibition may be particularly relevant. In a previous report modeling the relationship between the plasma levels of terazosin and pharmacodynamic effects in this model (Witte et al, 1997), the estimated plasma concentration of terazosin to produce 75% blockade was 100 ng/ml, which is equal to peak plasma levels achieved clinically with 5 mg of terazosin (Taguchi et al, 1998).…”

Preclinical Pharmacology of Fiduxosin, a Novel α1-Adrenoceptor Antagonist with Uroselective Properties

“…Thus, the clinical inadequacy of REC 15/2739 or Ro-70-0004 might have resulted from pharmacodynamic components and/or their lack of antagonistic action on ␣ 1D -adrenoceptors. In contrast, key pharmacological (selective blockade of both ␣ 1A -and ␣ 1D -adrenoceptors) and pharmacokinetic properties of fiduxosin (long half-life and prolonged in vivo efficacy; Witte et al, 2002) may contribute to a more favorable clinical profile.…”

Influence of hypertension on lower urinary tract symptoms in benign prostatic hyperplasia

“…Alpha-1 adrenergic receptor antagonists (alpha-1 antagonists) decrease the prostatic urethral closing pressure. [2][3][4][5][6] These antagonists have been used for the treatment of BPH, and can not only improve voiding disorders but also assist in the treatment of collecting disorders. 2,5,7 Among non-selective alpha-1 antagonists used for the treatment of BPH, terazosin hydrochloride (terazosin), prazosin hydrochloride, and urapidil have also been employed for the treatment of hypertension.…”