α_1-adrenoceptors are widely distributed in the human body and play important physiologic roles. Three α_1-adrenoceptor subtypes (α_<1A>, α_<1B> and α_<1D>) have been cloned and show different pharmacologic profiles. In addition, a putative α_1-adrenoceptor (α_<1L> 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 α_1-adrenoceptor subclassifications and the pharmacologic characteristics (subtype selectivity and clinical relevance) of α_1-adrenoceptor antagonists.
α_1-Adrenoceptor antagonists, called α_1-blockers, are the first-line treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). Nonselective α_1-blockers like prazosin were mainly used in the past, but prostate-specific α_1-blockers such as tamsulosin or naftopidil are now the mainstream agents for the management of BPH, based on the function of α_1-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 α_1-adrenoceptor (AR), to the subtypes (α_<1A>-, α_<1B>- and α_<1D>-ARs) was examined by a receptor-binding study and a functional pharmacological study, and we compared its subtype-selectivity with those of other α_1-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 α_1-AR subtypes was expressed. In the functional pharmacological study, the following isolated tissues were used as representative organs with high distribution densities of α_1-AR subtypes (α_<1A>-AR: rabbit prostate, urethra and bladder trigone; α_<1B>-AR: rat spleen; α_<1D>-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 α_<1A>-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 pA_2 or pKb values of 9.60, 8.71 and 9.35, respectively). On the other hand, the pA_2 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 α_1-AR antagonists. Our data suggest that silodosin has a high selectivity for the α_<1A>-AR subtype and for the lower urinary tract.
The effects of silodosin, an α_<1A>-adrenoceptor (AR) antagonist, and of other α_1-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 (30μg/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 4h [IUP being measured time-dependently following PE-injection (30μg/kg)], and IUP and BP were expressed as a percentage of the values without any drugs. ID_<50> for IUP and ED_<15> for BP were calculated, and uroselectivity was determined as ED_<15>/ID_<50> 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 (α_<1A>/α_<1D>-AR), naftopidil (α_<1D>-AR), or prazosin (non-selective α_1-AR). These results suggested that an α_<1A>-AR selective antagonist like silodosin might be effective in the LUT without causing hypotension.
We compared the urethral and cardiovascular effects of silodosin (selective α_<1A>-adrenoceptor antagonist), a novel medication for benign prostatic hyperplasia (BPH), with those of tamsulosin (selective α_<1A>/α_<1D>-adrenoceptor antagonist) and naftopidil (selective α_<1D>-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 (ED_<15> value for hypotensive effect/ID_<50> 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 30μg/kg, was infused (infusion rate: 36ml/h; infusion time: 100s/kg) via the femoral vein at 12h, 18h, or 24h 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 12h, 18h, and 24h after its oral administration (at doses of 100μg/kg and above, 1000μg/kg and above, and 3000μg/kg, respectively). On the other hand, tamsulosin hydrochloride showed no inhibitory action at 24h after its oral administration at doses up to 3000μg/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, C_<max> occurred within about 2h, indicating rapid absorption. The elimination half-life was about 2h in rat and dog, but 4.7h (fasted) and 6.0h (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 ^<14>C-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 α_1-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 ^<14>C-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 α_<1A>-adrenoceptor antagonist, was evaluated. The lethal doses were 800mg/kg in rats and 1500mg/kg in dogs. Repeated-dose studies revealed fatty degeneration of hepatocytes and an induction of drug-metabolizing enzymes at 15mg/kg/day or more in male rats, mammary gland hyperplasia at 60mg/kg/day or more in female rats, and degeneration of the seminiferous tubular epithelium at 25mg/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 150mg/kg/day or more and 400mg/kg/day respectively, while thyroid follicular cell carcinoma was increased in male rats given 150mg/kg/day. Reproductive studies in rats revealed a decreased male fertility at 20mg/kg/day or more and a prolonged estrous cycle at 60mg/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.