α1-adrenoceptors are widely distributed in the human body and play important physiologic roles. Three α1-adrenoceptor subtypes (α1A, α1B and α1D) have been cloned and show different pharmacologic profiles. In addition, a putative α1-adrenoceptor (α1L subtype) has also been proposed. Recently, three drugs (tamsulosin, naftopidil, and silodosin) have been developed in Japan for the treatment of urinary obstruction in patients with benign prostatic hyperplasia. In this review, we describe recent α1-adrenoceptor subclassifications and the pharmacologic characteristics (subtype selectivity and clinical relevance) of α1-adrenoceptor antagonists.
α1-Adrenoceptor antagonists, called α1-blockers, are the first-line treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). Nonselective α1-blockers like prazosin were mainly used in the past, but prostate-specific α1-blockers such as tamsulosin or naftopidil are now the mainstream agents for the management of BPH, based on the function of α1-adrenoceptor subtypes. Recent studies on voiding dysfunction have clarified the association between BPH and overactive bladder (OAB), underlining the use of OAB treatment in the management of BPH, inducing the simultaneous administration of antimuscarinic agents. Every aspect of diversified BPH symptom can be controlled individually in a short period.
The selectivity of silodosin (KMD-3213), an antagonist of α1-adrenoceptor (AR), to the subtypes (α1A-, α1B- and α1D-ARs) was examined by a receptor-binding study and a functional pharmacological study, and we compared its subtype-selectivity with those of other α1-AR antagonists. In the receptor-binding study, a replacement experiment using [3H]-prazosin was conducted using the membrane fraction of mouse-derived LM (tk-) cells in which each of three human α1-AR subtypes was expressed. In the functional pharmacological study, the following isolated tissues were used as representative organs with high distribution densities of α1-AR subtypes (α1A-AR: rabbit prostate, urethra and bladder trigone; α1B-AR: rat spleen; α1D-AR: rat thoracic aorta). Using the Magnus method, we studied the inhibitory effect of silodosin on noradrenaline-induced contraction, and compared it with those of tamsulosin hydrochloride, naftopidil and prazosin hydrochloride. Silodosin showed higher selectivity for the α1A-AR subtype than tamsulosin hydrochloride, naftopidil or prazosin hydrochloride (affinity was highest for tamsulosin hydrochloride, followed by silodosin, prazosin hydrochloride and naftopidil in that order). Silodosin strong antagonized noradrenaline-induced contractions in rabbit lower urinary tract tissues (including prostate, urethra and bladder trigone, with pA2 or pKb values of 9.60, 8.71 and 9.35, respectively). On the other hand, the pA2 values for antagonism of noradrenaline-induced contractions in rat isolated spleen and rat isolated thoracic aorta were 7.15 and 7.88, respectively. Selectivity for lower urinary tract was higher for silodosin than for the other α1-AR antagonists. Our data suggest that silodosin has a high selectivity for the α1A-AR subtype and for the lower urinary tract.
The effects of silodosin, an α1A-adrenoceptor (AR) antagonist, and of other α1-AR antagonists on the phenylephrine (PE)-induced increase in intraurethral pressure (IUP) and on blood pressure (BP) were studied in anesthetized rats. The drugs were administered intravenously (i.v. study) or intraduodenally (i.d. study). IUP and BP were measured via catheters inserted into the prostatic urethra and common carotid artery, respectively. In the i.v. study, drugs were administered every 30 min for effects on BP, and 5 min before each PE-injection (30 μg/kg, every 60 min) with stepwise increases in dose for effects on IUP. In the i.d. study, one dose of drug was administered per rat, then IUP and BP were observed for 4 h [IUP being measured time-dependently following PE-injection (30 μg/kg)], and IUP and BP were expressed as a percentage of the values without any drugs. ID50 for IUP and ED15 for BP were calculated, and uroselectivity was determined as ED15/ID50 for each drug. All drugs both inhibited the IUP increase and lowered BP, each effect being dose-dependent. The order of uroselectivities was silodosin (11.7)>tamuslosin (2.24)>naftopidil (0.133) in the i.v. study, and silodosin (26.0)>tamuslosin (3.82)>naftopidil (1.39) in the i.d. study. Selectivity for the lower urinary tract (LUT) was higher for silodosin than for tamsulosin (α1A/α1D-AR), naftopidil (α1D-AR), or prazosin (non-selective α1-AR). These results suggested that an α1A-AR selective antagonist like silodosin might be effective in the LUT without causing hypotension.
We compared the urethral and cardiovascular effects of silodosin (selective α1A-adrenoceptor antagonist), a novel medication for benign prostatic hyperplasia (BPH), with those of tamsulosin (selective α1A/α1D-adrenoceptor antagonist) and naftopidil (selective α1D-adrenoceptor antagonist). We evaluated the effects of these three drugs on the increase in intraurethral pressure (IUP) induced by electrical stimulation of the hypogastric nerve in anesthetized dogs with spontaneous BPH. All three drugs dose-dependently reduced both the increase in IUP and the mean blood pressure (MBP). The rank order of potencies was tamsulosin>silodosin>naftopidil for the reductions in both IUP and MBP. However, the uroselectivity (ED15 value for hypotensive effect/ID50 value for reduction in IUP) of silodosin (uroselectivity, 19.8) was about 21 and 4 times higher than that of tamsulosin (0.939) and naftopidil (4.94), respectively. These data suggest that silodosin might be one of the most useful medications for dysuria in BPH patients.
The duration of action of Silodosin (KMD-3213) against the phenylephrine-induced increase in intraurethral pressure in urethane-anesthetized rats was compared with that of tamsulosin hydrochloride. Silodosin, tamsulosin, or vehicle was orally administered to fasted male rats. Then, under urethane anesthesia, a cannula was inserted into the prostatic urethra. Phenylephrine, at a dose of 30 μg/kg, was infused (infusion rate: 36 ml/h; infusion time: 100 s/kg) via the femoral vein at 12 h, 18 h, or 24 h after administration of the study drug, and the intraurethral pressure in the prostate region was measured. Although the plasma silodosin concentration would have resolved within a few hours, silodosin significantly inhibited the phenylephrine-induced increase in intraurethral pressure (versus the vehicle-treated group) at 12 h, 18 h, and 24 h after its oral administration (at doses of 100 μg/kg and above, 1000 μg/kg and above, and 3000 μg/kg, respectively). On the other hand, tamsulosin hydrochloride showed no inhibitory action at 24 h after its oral administration at doses up to 3000 μg/kg. Thus, silodosin inhibits the phenylephrine-induced increase in intraurethral pressure for a longer time than tamsulosin hydrochloride.
After a single oral dose of silodosin in male rats, male dogs and healthy human male volunteers, Cmax occurred within about 2 h, indicating rapid absorption. The elimination half-life was about 2 h in rat and dog, but 4.7 h (fasted) and 6.0 h (non-fasted) in humans. Absolute bioavailability values in rat, dog and human were about 9, 25 and 32%, respectively. In rat and dog, total blood clearance was almost equivalent to the hepatic blood flow, but that in human was low (20%), demonstrating a large species difference in hepatic clearance. In each species, the apparent volume of distribution exceeded the volume of total body water. After an oral dose of 14C-silodosin to male rats, radioactivity was rapidly and widely distributed to most tissues. The highest concentrations outside the gastrointestinal tract were found in liver and kidney, with only low concentrations in brain tissues. The in vitro plasma protein binding of silodosin was about 80% in rat and dog, and 95.6% in humans, with α1-acid glycoprotein (AGP) contributing to the binding profile. Silodosin was found to be a dual substrate for CYP3A4 and p-glycoprotein. In human plasma, two major metabolites generated by UDP-glucuronosyltransferase (UGT; UGT2B7) and alcohol/aldehyde dehydrogenase (ADH/ALDH) were found, but no glucuronide conjugates were detected in rat or dog plasma. After a single oral dose of 14C-silodosin in rat, dog and human, the urinary excretion of radioactivity was 15—34%, with that of unchanged silodosin being less than 4%. The radioactivity was predominantly excreted via the feces.
The toxicity profile of silodosin, a selective α1A-adrenoceptor antagonist, was evaluated. The lethal doses were 800 mg/kg in rats and 1500 mg/kg in dogs. Repeated-dose studies revealed fatty degeneration of hepatocytes and an induction of drug-metabolizing enzymes at 15 mg/kg/day or more in male rats, mammary gland hyperplasia at 60 mg/kg/day or more in female rats, and degeneration of the seminiferous tubular epithelium at 25 mg/kg/day or more only in young dogs. Silodosin was negative in all mutagenicity studies, except for a weak positive in a chromosomal aberration assay conducted without metabolic activation. In carcinogenicity studies, mammary gland tumors and pituitary adenomas were increased in female mice given 150 mg/kg/day or more and 400 mg/kg/day respectively, while thyroid follicular cell carcinoma was increased in male rats given 150 mg/kg/day. Reproductive studies in rats revealed a decreased male fertility at 20 mg/kg/day or more and a prolonged estrous cycle at 60 mg/kg/day or more. Silodosin did not exhibit any teratogenic potential in either rats or rabbits, and had no effects on the postnatal development of rat offspring. In safety pharmacology studies, silodosin produced no severe effects on the central nervous, cardiovascular, or respiratory systems. In conclusion, silodosin exhibited adequate safety margins between the clinically recommended dose and those at which toxic effects or safety pharmacological changes were detected. As a new therapeutic drug for the micturition difficulties caused by benign prostatic hyperplasia, silodosin should have few serious side effects in clinical use.