The Pharmacological Profile of the a 1A -Adrenoceptor Antagonist Silodosin

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1 EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) available at journal homepage: The Pharmacological Profile of the a 1A -Adrenoceptor Antagonist Silodosin Martin C. Michel * Department of Pharmacology and Pharmacotherapy, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Article info Keywords: a 1 -adrenoceptor antagonists Pharmacology Selectivity Lower urinary tract symptoms Benign prostatic hyperplasia Abstract Silodosin, formerly known as KMD-3213, is a novel a-blocker for the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia. It has unprecedented selectivity for a 1A -adrenoceptors, as compared to both a 1B - and a 1D -adrenoceptors, exceeding selectivity of all currently used a-blockers. Such selectivity has been shown in vitro with cloned receptor subtypes as well as in a range of isolated human and animal tissues. It translates into in vivo functional uroselectivity in multiple animal species with efficacy against voiding dysfunction combined with a low degree of cardiovascular effects in both animals and patients. These properties make silodosin a clinically promising new agent. # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Department of Pharmacology and Pharmacotherapy, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Tel ; Fax: address: m.c.michel@amc.nl. a 1 -Adrenoceptor antagonists (a-blockers) are one of the most effective forms of medical treatment to reduce symptoms in most men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH; LUTS/BPH). They are considered an appropriate treatment option by AUA, based on their treatment outcomes analysis [1]. Numerous indirect comparisons between placebo-controlled studies of individual drugs as well as a more limited number of direct comparative studies have demonstrated that all a-blockers are similarly effective when adequate dosages are used [2]. Alternatively, the various available a-blockers may differ in tolerability. In particular, the a 1A -selective tamsulosin appears to have a somewhat better tolerability than several a-blockers without subtype selectivity such as doxazosin or terazosin [3], specifically with regard to cardiovascular side effects [4]. Silodosin, previously known as KMD-3213, is a novel a-blocker for the treatment of LUTS/BPH with an unprecedented degree of selectivity for a 1A -adrenoceptors. This manuscript will review the pharmacologic profile of silodosin, particularly with regard to its efficacy and tolerability profile. 1. Selectivity for a 1A -adrenoceptors Contraction of the human prostate, believed to be an important contributor to LUTS/BPH, is mediated predominantly, if not exclusively, by a 1A -adrenoceptors [5], indicating that selective blockade of this subtype may be sufficient for effective treatment of LUTS/BPH. In contrast, all three a 1 -adrenoceptor subtypes can contribute to vasoconstriction [6], and specifically in the elderly, the functional role of a 1B -adrenoceptors may increase further [7]. This indicates that a drug with selectivity for a 1A -adrenoceptors may cause fewer adverse cardiovascular effects than drugs without a 1A -adrenoceptor selectivity but may not necessarily be fully free of cardiovascular effects. Although all a-blockers from the quinazoline family including alfuzosin, doxazosin, prazosin, and terazosin lack selectivity for any of the a 1 -adrenoceptor subtypes, tamsulosin is moderately selective for a 1A -adrenoceptors over a 1B -adrenoceptors (about 10- to 15-fold) with intermediate affinities for a 1D -adrenoceptors [8] (Fig. 1). In contrast, multiple studies using cloned human subtypes have demonstrated that silodosin is highly selective for /$ see front matter # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eursup

2 EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) Fig. 1 Affinities of prazosin, silodosin, and tamsulosin at cloned a 1 -adrenoceptor subtypes as reported by two independent laboratories. Note that a high graph indicates a high affinity on a logarithmic scale. Adapted from Shibata et al. [9] and Tatemichi et al. [12]. humans [5]. Importantly, silodosin has similarly high affinity and selectivity for the a 1A -adrenoceptors in both its classical and a 1L phenotype [10,17,19,20]. Moreover, silodosin has similarly high affinity for splice variants of the a 1A -adrenoceptor [22]. The a 1A selectivity of silodosin has also been tested functionally using isolated tissues from various mammalian species including humans. Those studies have included contraction studies in prototypical a 1A tissues, such as rat caudal artery [10], rabbit prostate [23], rabbit iris dilator muscle [13], dog prostate [24], human vas deferens [25] and human prostate [15,26], as well as hypertrophy induction in rat cardiomyocytes [27]. In contrast, silodosin inhibited with much lower potency, typical a 1B responses including contraction of dog carotid artery [10,24] and human mesenteric artery [15] and typical a 1D responses including contraction of rat aorta [10,23]. In all cases, silodosin was found to have much higher affinity for a 1A -adrenoceptors including its a 1L phenotype [12,23] compared to a 1B - and a 1D -adrenoceptors, its affinities being in good agreement with those reported from the radioligand binding studies with cloned subtypes and tissue homogenates. Studies with cloned a 1A - and a 1B -adrenoceptor subtypes have demonstrated that a-blockers from the quinazoline family are inverse agonists, whereas silodosin and tamsulosin are neutral antagonists [28,29]. Accordingly, chronic treatment with the quinazoline a-blocker prazosin caused a 1 -adrenoceptor upregulation in various rat tissues, whereas similar treatment with silodosin did not [30]. a 1A -adrenoceptors compared to both a 1B -ora 1D -adrenoceptors [9 12]. Thus, silodosin not only has considerably greater selectivity for a 1A -adrenoceptors over a 1B -adrenoceptors (>100-fold) but also is selective for a 1A -adrenoceptors over a 1D -adrenoceptors (about 50-fold) (Fig. 1). Such selectivity for a 1A -adrenoceptors over both a 1B - and a 1D -adrenoceptors has been confirmed in radioligand binding studies with various tissues from several mammalian species including human prostate [9 17]. Accordingly, radiolabeled silodosin has become a standard tool for the selective labeling of a 1A -adrenoceptors in tissues [15,18 20]. On intravenous injection of tritiated silodosin into rats, the drug exhibited long-lasting specific binding in a 1A tissues such as submaxillary gland, vas deferens, and prostate, whereas its binding to a 1B/D tissues including aorta, spleen, and liver was much lower than that of tritiated prazosin, thereby biochemically confirming its a 1A selectivity in vivo [18,21]. Moreover, little tritiated silodosin was detected in the brain, indicating a lack of penetration through the blood brain barrier and, hence, very low potential for centrally mediated side effects. The a 1 -adrenoceptors in some tissues exhibit a surprisingly low affinity for prazosin and related quinazoline-type a-blockers, and this is often referred to as an a 1L -receptor. More recent work shows that the a 1L -receptor is not a distinct subtype but rather represents a phenotype of the a 1A -adrenoceptor. The a 1L phenotype has been implicated in prostatic contraction in rabbits and, to a lesser degree, 2. Pharmacodynamic effects Based on a moderate subtype selectivity of tamsulosin, there have been questions about whether a highly selective a 1A -adrenoceptor blockade will be sufficient to treat voiding dysfunction. Silodosin, however, improved pressure flow study outcomes in hormone- and obstruction-induced rat BPH models [31,32] and symptoms in clinical studies [33]. Interestingly, silodosin may work not only at the level of prostatic smooth muscle but also on bladder afferent nerves, thereby specifically targeting bladder overactivity and storage symptoms [34]. Additional studies have been designed to test the functional uroselectivity of silodosin in vivo. In urethrane-anesthetized rats the effects of silodosin and other a-blockers were compared for inhibition of phenylephrine-induced elevation of intraurethral pressure and for lowering of blood pressure [35]. In this model, silodosin exhibited functional uroselectivity that exceeded that of other a-blockers including tamsulosin. A greater functional uroselectivity with silodosin as compared with tamsulosin has also been reported in anesthetized [24,36] or decerebrate dogs [37]. In another dog study, silodosin did not affect blood pressure, heart rate, or electrocardiogram unless vastly supratherapeutic doses were administered [38]. Notably, in all of these in vivo models, functional uroselectivity was smaller than expected based on silodosin s a 1A -adrenoceptor selectivity but nevertheless exceeded that of the various comparator drugs including

3 488 EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) tamsulosin. Accordingly, silodosin also exhibited smaller potential for causing orthostatic hypotension in anesthetized rats than prazosin or tamsulosin [39]. 3. Undesirable effects Abnormal ejaculation, often referred to as retrograde ejaculation, is a potential side effect of a-blockers. It has become clear that this represents (relative) anejaculation rather than retrograde ejaculation [40,41]. Because this side effect has been observed more frequently with tamsulosin than with other a-blockers [40], it has been speculated that the side effect may be associated with selective a 1A -adrenoceptor antagonism. Abnormal ejaculation has also been observed frequently with silodosin [33,42], but the clinical relevance of this occurrence remains unclear, as subjects experiencing abnormal ejaculation during treatment with tamsulosin or silodosin are not more likely to discontinue treatment and, if anything, exhibit greater symptom reduction [43,44]. A rare but possible adverse event related to a-blockers is observed only during cataract surgery and has been named intraoperative floppy iris syndrome [45]. This adverse event may occur more frequently with tamsulosin than with other a-blockers, but it is not fully clear whether this event is related to selectivity for a 1A -adrenoceptors [13]. To date, no cases of intraoperative floppy iris syndrome have been reported with silodosin in Europe, although a few cases were reported in Japan. An experimental study in rabbits has shown that the ratio between doses altering pupil function and those affecting urethral function (a proxy parameter for treatment effects on LUTS/BPH) is very similar for silodosin compared to many other a-blockers [46]. Thus, among all clinically used a-blockers, silodosin has, by far, the greatest selectivity for the a 1A -adrenoceptor. This selectivity may contribute to a higher degree of functional uroselectivity in experimental animals than with previously used a-blockers, including tamsulosin, as well as to good cardiovascular tolerability, as reported in clinical studies [33,42]. It may, however, also contribute to a higher incidence of abnormal ejaculation. 4. Pharmacokinetics Studies with both alfuzosin (not subtype selective) and tamsulosin (moderately a 1A selective) have demonstrated that in addition to subtype selectivity, factors such as selective partitioning into urogenital tissues and a smooth pharmacokinetic profile may also contribute to good tolerability of a-blockers [47]. In rat studies with intravenous injection of tritiated silodosin, the drug was retained for a much longer time in vas deferens and prostate than in aorta, spleen, heart, lung, kidney, or plasma [18,48]. Notably, the inhibition of phenylephrine-induced elevations of intraurethral pressure was correlated with prostate binding of silodosin [49]. Thus, silodosin may share the selective partitioning into urogenital tissues previously reported for alfuzosin and tamsulosin. With regard to a smooth pharmacokinetic profile, the clinically available formulation reaches maximal plasma concentrations after about 2.6 h, which is somewhat faster than observed with tamsulosin [50], and has a half-life of about 13 h [51]. 5. Conclusions In conclusion, silodosin is a novel a-blocker for the treatment of LUTS/BPH. It has unsurpassed selectivity for a 1A -adrenoceptors in biochemical and functional in vitro studies and also has unsurpassed functional uroselectivity in rat and dog models in vivo. Moreover, silodosin appears to be retained longer in prostate than in many other tissues or plasma, and this retention may also contribute to functional uroselectivity. All of these preclinical features may contribute to overall small cardiovascular effects in patients. Conflicts of interest In recent years the author has received research support, consultancy fees, and/or lecturer honoraria in the field of a 1 -adrenoceptors from the following companies: Astellas, Boehringer Ingelheim, Recordati, and Schwarz Pharma. Funding support None. References [1] Roehrborn CG, Mc Connel J, Barry MJ, et al. Guideline on the Management of Benign Prostatic Hypertrophy. AUA website: clinical-guidelines/main-reports/bph-management/preface_toc.pdf. [2] Milani S, Djavan B. Lower urinary tract symptoms suggestive of benign prostatic hyperplasia: latest updated on a 1 -adrenoceptor antagonists. BJU Int 2005;95(Suppl 4): [3] van Dijk MM, de la Rosette JJMCH, Michel MC. Tamsulosin modified-release and oral-controlled absorption system formulation in the treatment of benign prostatic hyperplasia. Therapy 2006;3: [4] Nickel JC, Sander S, Moon TD. 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