Modeling of Relationships between Pharmacokinetics and Blockade of Agonist-Induced Elevation of Intraurethral Pressure and Mean Arterial Pressure in Conscious Dogs Treated with 1-Adrenoceptor Antagonists

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 IC50 values for terazosin, doxazosin, tamsulosin, and fiduxosin were 48.6, 48.7, 0.42, and 261 ng/ml, respectively. MAP IC50 values were 12.2, 13.8, 1.07, and 1904 ng/ml, respectively. Uroselectivity index values, defined as MAP IC50/IUP IC50, 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, 2002), showing fiduxosin to be selective for 1aand 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-adrenoceptors (Bylund et al., 1994). The findings of enrichment of 1A-adrenoceptors in human prostate gland stimulated interest in identifying 1Aselective, and by extrapolation “prostate-selective”, antagoABBREVIATIONS: BPH, benign prostatic hyperplasia; fiduxosin (ABT-980), (3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexa-hydro[1]benzopyrano[3,4-c]pyrrol-2-yl)butyl]-8-phenyl-pyrazino[2 ,3 :4,5]thieno-[3,2-d]pyrimidine-2,4(1H,3H)-dione)); REC 15/2739, (N-[3-[4-(2methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxamide); PE, phenylephrine; MAP, mean arterial pressure; IUP, intra-urethral pressure; PK, pharmacokinetics; PD, pharmacodynamics; TFA, trifluoroacetic acid; A-86192 (N-[2-benzofuran-6-yl)ethyl]-N-[(R)-5,6methylenedioxy-1,2,3,4-tetra-hydronaphthalen-1-ylmethyl]-N-methylamine mathanesulfonate); A-131701 (3-[2-((3aR,9bR)-cis-6-methoxy2,3,3a,4,5,9b,hexa-hydro-[1H]-benz[e]isoindol-2-yl)ethyl]pyrido[3 ,4 :4,5]thieno[3,2-d]-pyrimidino-2,4(1H,3H)-dione); LC-MS, liquid chromatographymass spectrometry; RSD, relative standard deviation; CL/F, oral plasma clearance/oral bioavailability; ANOVA, analysis of variance; AUC0, area under the plasma concentration-time curve; AUCE, area under the effect against time curve. 0022-3565/02/3002-495–504$3.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 300, No. 2 Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics 4358/960504 JPET 300:495–504, 2002 Printed in U.S.A. 495 at A PE T Jornals on Sptem er 8, 2017 jpet.asjournals.org D ow nladed from nists to ameliorate BPH symptoms and to reduce adverse effects (e.g., decreased blood pressure, postural hypotension, or syncope) observed with nonsubtype-selective 1-antagonists such as doxazosin or terazosin (Lowe, 1999). However, REC 15/2739, a compound showing high 1A-adrenoceptor selectivity, failed to ameliorate BPH symptoms in clinical trials (Lowe, 1999), perhaps the result of poor pharmacokinetic properties (A. A. Hancock and S. A. Buckner, unpublished data). Thus, the hypothesis of 1A-selectivity correlating to clinical uroselectivity remains unproved. Interest in the role of 1D-adrenoceptors in the lower urinary tract has increased based on studies showing that this subtype predominates in human bladder (Lowe, 1999; Schwinn and Michelotti, 2000) and may play a role in detrusor instability (Fitzpatrick, 2000; Schwinn and Michelotti, 2000), a frequent and major component of BPH symptomatology (DeMey, 1999). Cardiovascular sequelae of 1-adrenoceptor blockade are generally attributed to actions primarily at 1B-adrenoceptors, because neither 1Anor 1D-adrenoceptors appear to predominate in any vascular bed (DeMey 1999). Although selective 1A-adrenoceptor antagonists have been shown to potently block increases of noradrenaline-induced resistance in isolated preparations, effects on MAP are observed only with very high doses, suggesting some non1A-adrenoceptors regulate blood pressure control. (Hieble and Ruffolo, 1997). In addition, the ratio of 1Ato 1B-adrenoceptors decreases with age in blood vessels (Fitzpatrick, 2000), suggesting that vascular function could be maintained in the absence of blockade of 1B-adrenoceptors (Fitzpatrick, 2000). Thus, compounds that are highly selective for the 1A-/ 1Dsubtypes relative to 1B-adrenoceptors could have the potential for enhanced clinical uroselectivity compared with available 1-adrenoceptor antagonists (DeMey, 1999; Fitzpatrick, 2000; Schwinn and Michelotti, 2000). A challenge for experimental therapeutics is to establish models of uroselectivity predictive for clinical BPH. Several animal models have been previously used toward this end, having the benefit of using intact animals to include extraprostatic influence on efficacy measurements, with the most appropriate functional models based on the dog. Canine prostate surrounds and impinges upon the urethra with advancing age as seen in human (DeKlerk et al., 1979), and the pharmacology of canine 1-adrenoceptors also resembles human (Hieble et al., 1986; Lepor et al., 1992). First attempts in the anesthetized dog measured the potency of 1-antagonists to block agonist-induced increases in blood and intraurethral pressures (Kenny et al., 1994; Brune et al., 1995). Limitations of these methods include the acute nature of the experiments, the necessity for intravenous drug administration, and the inability to incorporate pharmacokinetic considerations into the experimental design. These factors may have contributed to the difficulty in demonstrating functional selectivity of 1-antagonists evaluated therein (Kenny et al., 1994; Brune et al., 1995). Subsequently, a conscious dog model was developed (Brune et al., 1996), featuring oral administration of compounds and evaluation of the antagonism of vascular and urethral 1adrenoceptors with stimulation by phenylephrine (PE) over time. Analysis of mean arterial (MAP) and intraurethral pressure (IUP) responses, coupled with quantification of plasma levels of terazosin provided a pharmacokinetic (PK) and pharmacodynamic (PD) profile consistent with the clinical attributes of this nonsubtype-selective 1-adrenoceptor antagonist (Witte et al., 1997). More recently, however, pharmacodynamic analysis of data from the conscious canine model has been used to evaluate the potential uroselectivity of novel 1-adrenoceptor antagonists (Hancock et al., 1998). In the present study we compared the PK and PD properties of four 1-adrenoceptor antagonists. These included the nonselective antagonists terazosin and doxazosin; the 1A-/ 1Dadrenoceptor-selective antagonist tamsulosin, reported in comparative studies to show uroselectivity (Lee and Lee, 1997; Schäfers et al., 1999; Tsujii, 2000); and a novel 1A-/ 1D-adrenoceptor-selective antagonist fiduxosin. PK/PD modeling of these data provide a basis for evaluating the potential uroselectivity of fiduxosin compared with nonselective 1-antagonists. Materials and Methods