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Pharmaceuticals -> Listed in ZINC15

Pharmaceutical

2.3

2.2

Sparingly soluble in water

6.55e-03 g/L

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl tamsulosin hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Tamsulosin hydrochloride/

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The effects of cimetidine at the highest recommended dose (400 mg every six hours for six days) on the pharmacokinetics of a single tamsulosin hydrochloride capsule 0.4 mg dose was investigated in ten healthy volunteers (age range 21-38 years). Treatment with cimetidine resulted in a significant decrease (26%) in the clearance of tamsulosin hydrochloride which resulted in a moderate increase in tamsulosin hydrochloride AUC (44%). Therefore, Tamsulosin hydrochloride capsules should be used with caution in combination with cimetidine, particularly at doses higher than 0.4 mg.

Results from limited in vitro and in vivo drug-drug interaction studies between tamsulosin hydrochloride and warfarin are inconclusive. Therefore, caution should be exercised with concomitant administration of warfarin and tamsulosin hydrochloride capsules.

... Interactions between the two drugs were evaluated in rats after simultaneous 1 or 15 min iv infusion or after po administration of udenafil (30 mg x kg(-1)) and/or tamsulosin (1 mg x kg(-1)). In vitro metabolism of tamsulosin with udenafil was measured to obtain the inhibition constant (K(i)) and [I]/K(i) ratio of udenafil. The total area under the plasma concentration-time curve from time zero to time infinity (AUC)s (or AUC(0-4 h)) of tamsulosin were significantly greater after 15 min of i.v. infusion or after oral administration with udenafil, compared with tamsulosin alone. The hepatic first-pass metabolism of tamsulosin was inhibited by udenafil, and the inhibition in vitro was in a non-competitive mode. The arterial systolic blood pressure was significantly lower at 5, 10 and 60 min after oral co-administration of the drugs. The significantly greater AUC of tamsulosin after i.v. and p.o. administration of both drugs may be attributable to non-competitive inhibition of cytochrome P450 3A1/2-mediated hepatic tamsulosin metabolism by udenafil. The inhibition was also observed in human liver S9 fractions, suggesting that a reassessment of the oral dosage of tamsulosin is necessary when udenafil and tamsulosin are co-administered to patients with benign prostatic hyperplasia.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 3.0X10+4(SRC), determined from a structure estimation method(2), indicates that tamsulosin is expected to be immobile in soil(SRC). Volatilization of tamsulosin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 4.9X10-15 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Tamsulosin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.0X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2009).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 3.0X10+4(SRC), determined from a structure estimation method(2), indicates that tamsulosin is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 4.9X10-15 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 20(SRC), from an estimated log Kow of 2.5(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2009).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), tamsulosin, which has an estimated vapor pressure of 4.0X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase tamsulosin may be removed from the air by wet or dry deposition(SRC). Tamsulosin does not contain chromophores that absorb at wavelengths >290 nm(3) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of tamsulosin can be estimated to be 3.0X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that tamsulosin is expected to be immobile in soil.

/HUMAN EXPOSURE STUDIES/ To assess whether tamsulosin has any effect on semen, sperm parameters were evaluated in healthy men receiving tamsulosin, alfuzosin, and placebo. Forty-eight healthy men received 5 days of tamsulosin 0.8 mg once daily (QD), alfuzosin 10 mg QD, and placebo in a randomized, double-blind, 3-way crossover study with a 10-14-day washout period between treatments. The mean (SE) changes from baseline in semen sperm concentration, semen sperm count, semen viscosity, semen fructose, sperm motility, and sperm morphology on Day 5 of treatment were assessed. The change from baseline in semen sperm concentration was 3.1 (8.3) million/mL with tamsulosin, 15.0 (6.5) million/mL with alfuzosin, and 24.4 (6.5) million/mL with placebo. The total sperm count in semen decreased from baseline with tamsulosin [-54.6 (24.0) million] but not with placebo [81.5 (18.8) million] or alfuzosin [46.2 (19.0) million]. The percentage of men with normal semen viscosity was lower with tamsulosin (65%) than with placebo (98%) or alfuzosin (92%). The change from baseline in semen fructose was comparable for all treatments. The percentage of motile sperm decreased 13.8% from baseline to Day 5 of treatment with tamsulosin compared with decreases of 2.3% with placebo and 0.4% with alfuzosin. The percentage of abnormal sperm increased marginally with tamsulosin (0.6%) but not with placebo (-2.8%) or alfuzosin (-3.9%). The most common adverse events were dizziness (alfuzosin 11%, tamsulosin 14%, placebo 0%) and orthostatic hypotension (alfuzosin 25%, tamsulosin 11%, placebo 5%). The results suggest that tamsulosin has a negative impact on sperm in healthy men. ...

/SIGNS AND SYMPTOMS/ One patient reported an overdose of thirty 0.4 mg tamsulosin hydrochloride capsules. Following the ingestion of the capsules, the patient reported a severe headache.

/CASE REPORTS/ A 65-year-old man underwent uncomplicated cataract extraction and placement of a posterior chamber intraocular lens. The patient subsequently developed three separate episodes of choroidal detachments in the operated eye. Each episode was preceded by treatment with an alpha(1)-adrenoceptor antagonist. Tamsulosin may cause adverse ocular effects including recurrent choroidal detachments ... The mechanism for choroidal detachment in this patient could include some effect of antagonists like tamsulosin on these receptors.

/CASE REPORTS/ /Investigators/ describe the case of an 80-year-old patient who was started on alpha blocker treatment after acute urinary retention with the aim to perform a voiding test. The patient presented self-limited episodes of disorientation in time and space and abnormal behavior in coincidence with the first three administrations of the drug. Treatment was stopped. ...

For more Human Toxicity Excerpts (Complete) data for Tamsulosin (12 total), please visit the HSDB record page.

Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)

tamsulosin

Flomax®

Antiadrenergics

Not Applicable

no-DILI-concern

An estimated BCF of 20 was calculated in fish for tamsulosin(SRC), using an estimated log Kow of 2.5(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for tamsulosin is estimated as 4.9X10-15 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that tamsulosin is expected to be essentially nonvolatile from water surfaces(2). Tamsulosin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.0X10-11 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Mice were administered doses /of tamsulosin hydrochloride/ up to 127 mg/kg/day in males and 158 mg/kg/day in females. There were no significant tumor findings in male mice. Female mice treated for 2 years with the two highest doses of 45 and 158 mg/kg/day had statistically significant increases in the incidence of mammary gland fibroadenomas (P<0.0001) and adenocarcinomas (P<0.0075). The highest dose levels of tamsulosin hydrochloride evaluated in the mice carcinogenicity study produced systemic exposures (AUC) in mice 8 times the exposures in men receiving the maximum therapeutic dose of 0.8 mg/day.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Rats administered doses up to 43 mg/kg/day in males and 52 mg/kg/day in females had no increases in tumor incidence with the exception of a modest increase in the frequency of mammary gland fibroadenomas in female rats receiving doses greater than or equal to 5.4 mg/kg (P <0.015). The highest doses of tamsulosin hydrochloride evaluated in the rat carcinogenicity study produced systemic exposures (AUC) in rats 3 times the exposures in men receiving the maximum therapeutic dose of 0.8 mg/day.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ This study examined the antifertility effects of tamsulosin, a highly potent and a selective, alpha 1-adrenoceptor antagonist, on male rats. The drug was administered subcutaneously as a single dose (0.15 mg kg-1). The drug caused a significant reduction in fertility (measured by number of uterine implants, quantal pregnancy, and fertility index). The antifertility effect was short lived and rapid in both onset (no later than 7 hr of administration) and recovery (within 7 days). Libido and mating performance remained essentially uninhibited. On the other hand, the antifertility effect was accompanied by significant impairment in ejaculatory competence and enhancement of pre-implantation losses. Based on the results of this study and our previous studies it is concluded that alpha 1-adrenoceptor blockade has a potent antifertility effect in male rats.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Studies in female rats revealed significant reductions in fertility after single or multiple dosing with 300 mg/kg/day of the R-isomer or racemic mixture of tamsulosin hydrochloride, respectively. In female rats, the reductions in fertility after single doses were considered to be associated with impairments in fertilization. Multiple dosing with 10 or 100 mg/kg/day of the racemic mixture did not significantly alter fertility in female rats.

For more Non-Human Toxicity Excerpts (Complete) data for Tamsulosin (8 total), please visit the HSDB record page.

Tamsulosin is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Tamsulosin does not contain chromophores that absorb at wavelengths >290 nm(1) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Occupational exposure to tamsulosin may occur through inhalation and dermal contact with this compound at workplaces where tamsulosin is produced or used. Exposure to tamsulosin among the general male population may be limited to those administered the drug Flomax, an alpha-1 adrenoreceptor blocker. (SRC)

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl tamsulosin hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Tamsulosin hydrochloride/

G04CA02

G - Genito urinary system and sex hormones

QG - Genito urinary system and sex hormones

Tamsulosin is an alpha adrenoceptor blocker with specificity for the alpha-1A and alpha-1D subtypes, which are more common in the prostate and submaxillary tissue. The final subtype, alpha-1B, are most common in the aorta and spleen. Tamsulosin binds to alpha-1A receptors 3.9-38 times more selectively than alpha-1B and 3-20 times more selectively than alpha-1D. This selectivity allows for a significant effect on urinary flow with a reduced incidence of adverse reactions like orthostatic hypotension.

Tamsulosin is a blocker of alpha-1A and alpha-1D adrenoceptors. About 70% of the alpha-1 adrenoceptors in the prostate are of the alpha-1A subtype. By blocking these adrenoceptors, smooth muscle in the prostate is relaxed and urinary flow is improved. The blocking of alpha-1D adrenoceptors relaxes the detrusor muscles of the bladder which prevents storage symptoms. The specificity of tamsulosin focuses the effects to the target area while minimizing effects in other areas.

Tamsulosin hydrochloride is a sulfamoylphenethylamine-derivative alpha1-adrenergic blocking agent. The drug is pharmacologically related to doxazosin, prazosin, and terazosin; however, unlike these drugs, tamsulosin has higher affinity and selectivity for alpha1A-adrenergic receptors, which are mainly located in nonvascular smooth muscle (eg, prostate), than for alpha1B-adrenergic receptors located in vascular smooth muscle (eg, internal iliac artery). Results of in vitro studies indicate that tamsulosin has 7-38 times greater affinity for alpha1A-adrenoceptors than for alpha1B-adrenoceptors; the drug has about 12 times greater affinity for alpha1-adrenergic receptors in the prostate than for those in the aorta. Such selectivity of tamsulosin for alpha1A-receptors may result in a reduced incidence of adverse cardiovascular effects (eg, syncope, dizziness, hypotension). On a molar basis, the alpha1-adrenergic receptor affinity of tamsulosin is about 6 times that of prazosin when tested in human prostatic tissue.

Because of the prevalence of alpha-receptors on the prostate capsule, prostate adenoma, and bladder trigone and the relative absence of these receptors on the bladder body, alpha-adrenergic blocking agents decrease urinary outflow resistance in men.

The symptoms associated with benign prostatic hyperplasia (BPH) are related to bladder outlet obstruction, which is comprised of two underlying components: static and dynamic. The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck leading to constriction of the bladder outlet. Smooth muscle tone is mediated by the sympathetic nervous stimulation of alpha1 adrenoceptors, which are abundant in the prostate, prostatic capsule, prostatic urethra, and bladder neck. Blockade of these adrenoceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of BPH.

The influence of (+/-)-tamsulosin, a selective alpha 1A-adrenoceptor antagonist, on the positive inotropic effect and the accumulation of inositol phosphates that are induced via alpha 1-adrenoceptors was studied in comparison with that of another alpha 1A-adrenoceptor ligand oxymetazoline in the rabbit ventricular myocardium. Phenylephrine elicited a concentration-dependent positive inotropic effect via alpha 1-adrenoceptors in the presence of either (+/-)-bupranolol or S(-)-timolol. The mode of antagonism induced by (+/-)-tamsulosin on the effect of phenylephrine was dependent or the concentration applied: (+/-)-tamsulosin at 1 and 3 nM acted in a competitive manner, the slope of the regression line of the Schild plot being unity and the pA2 value being 9.12; at 10 nM, it shifted further the concentration-response curve to the right without affecting the maximal response but the slope became less than unity. At 100 nM and higher, it suppressed the maximal response to phenylephrine. (+/-)-Tamsulosin effectively antagonized the positive inotropic effect of phenylephrine even after inactivation of alpha 1B-adrenoceptors by treatment with chlorethylclonidine, which is an indication that the (+/-)-tamsulosin-sensitive subtype belongs to a class resistant to chlorethylclonidine. (+/-)-Tamsulosin, over the range of concentrations at which it antagonized the positive inotropic effect mediated by alpha 1-adrenoceptors, did not affect the accumulation of [3H]inositol phosphates that was induced by 10 microM phenylephrine. Oxymetazoline antagonized the positive inotropic effect of phenylephrine in a competitive manner without affecting the accumulation of inositol monophosphate induced by phenylephrine. These results indicate that the positive inotropic effect, mediated via (+/-)-tamsulosin- and oxymetazoline-sensitive subtype of alpha 1-adrenoceptors, is exerted by a subcellular mechanism that is independent of the accumulation of inositol phosphates.

The half life in fasted patients is 14.9±3.9 hours. The elimination half life is 5-7 hours and the apparent half life is 9 to 13 hours in healthy subjects. In patients who require tamsulosin, the apparent half life is 14-15 hours.

Following intravenous or oral administration of an immediate-release formulation, the elimination half-life of tamsulosin hydrochloride in plasma range from five to seven hours.

Because of absorption rate-controlled pharmacokinetics of tamsulosin capsules, apparent half-life is about 9-13 hours in healthy individuals and 14-15 hours in patients with benign prostatic hyperplasia.

The pharmacokinetics of tamsulosin hydrochloride was investigated after single iv and oral dosing to rats and dogs, and oral dosing to healthy male volunteers. After iv dosing, plasma tamsulosin concentrations declined in an apparent biexponential manner with terminal half-lives of 0.32 hr in rats and 1.13 hr in dogs. ...

Tamsulosin is mostly metabolized in the liver by cytochrome P450 (CYP) 3A4 and 2D6, with some metabolism by other CYPs. CYP3A4 is responsible for the deethylation of tamsulosin to the M-1 metabolite and the oxidative deamination to the AM-1 metabolite, while CYP2D6 is responsible for the hydroxylation of tamsulosin to the M-3 metabolite and the demethylation of tamsulosin to the M-4 metabolite. In addition, tamsulosin can be hydroxylated at a different position by an unknown enzyme to form the M-2 metabolite. The M-1, M-2, M-3, and M-4 metabolites can be glucuronidated, and the M-1 and M-3 metabolites can undergo sulfate conjugation to form other metabolites before excretion.

Extensively metabolized by CYP enzymes (specific isoenzyme[s] not identified) in the liver. Metabolites undergo further conjugation prior to excretion.

There is no enantiomeric bioconversion from tamsulosin hydrochloride [R(-) isomer] to the S(+) isomer in humans. Tamsulosin hydrochloride is extensively metabolized by cytochrome P450 enzymes in the liver and less than 10% of the dose is excreted in urine unchanged. However, the pharmacokinetic profile of the metabolites in humans has not been established. In vitro results indicate that CYP3A4 and CYP2D6 are involved in metabolism of tamsulosin as well as some minor participation of other CYP isoenzymes. Inhibition of hepatic drug metabolizing enzymes may lead to increased exposure to tamsulosin. The metabolites of tamsulosin hydrochloride undergo extensive conjugation to glucuronide or sulfate prior to renal excretion.

... After a single oral administration of 14C-tamsulosin at a dose of 0.2 mg /to/ four healthy male subjects... unchanged tamsulosin (TMS) and 11 metabolites in 0-24-hr urine samples were quantified. TMS accounted for 8.7% of the dose. Extensive excretion of the sulphate of the O-deethylated metabolite (M-1-Sul) and o-ethoxyphenoxy acetic acid (AM-1) was seen, accounting for 15.7 and 7.5% of the dose respectively.

The metabolism of tamsulosin hydrochloride (TMS), a potent alpha 1-adrenoceptor blocking agent, was studied after a single oral administration to rat and dog. Eleven metabolites (1, 2, 3, 4 and their glucuronides, sulphates of 1 and 3, and A-1) were identified from the urine and bile of rat and dog administered TMS. Unchanged drug and metabolites in urine and bile were quantified in rat and dog dosed with 14C-TMS(1 mg/kg). In rat the main metabolic routes were de-ethylation of the o-ethoxyphenoxy moiety, demethylation of the methoxybenzenesulphonamide moiety, and conjugation of the resultant metabolites by glucuronic acid and sulphuric acid. In dog the main pathways were de-ethylation of the ethoxyphenoxy moiety, conjugation of the de-ethylated product by sulphuric acid, and oxidative deamination of the side chain. The organ responsible for the metabolism of TMS in rat was estimated using 9000g supernatants of liver, kidney, small and large intestine homogenate and plasma. The drug was rapidly metabolized in liver but hardly metabolized in the other organs or plasma.

For more Metabolism/Metabolites (Complete) data for Tamsulosin (6 total), please visit the HSDB record page.

G3P28OML5I

TAMSULOSIN

Mechanisms of Action [MoA] - Adrenergic alpha-Antagonists

Established Pharmacologic Class [EPC] - alpha-Adrenergic Blocker

Tamsulosin is an alpha-Adrenergic Blocker. The mechanism of action of tamsulosin is as an Adrenergic alpha-Antagonist.

Drugs that bind to and block the activation of ADRENERGIC ALPHA-1 RECEPTORS.

Drugs used in the treatment of urological conditions and diseases such as URINARY INCONTINENCE and URINARY TRACT INFECTIONS.

Oral tamsulosin is 90% absorbed in fasted patients. The area under the curve is 151-199ng/mL\*hr for a 0.4mg oral dose and 440-557ng/mL*hr for a 0.8mg oral dose. The maximum plasma concentration is 3.1-5.3ng/mL for a 0.4mg oral dose and 2.5-3.6ng/mL for a 0.8mg oral dose. Taking tamsulosin with food increases the time to maximum concentration from 4-5 hours to 6-7 hours but increases bioavailability by 30% and maximum plasma concentration by 40-70%.

97% of an orally administered does is recovered in studies, which 76% in the urine and 21% in the feces after 168 hours. 8.7% of the dose is excreted as unmetabolized tamsulosin.

16L after intravenous administration.

2.88L/h.

In patients with moderate hepatic impairment, protein binding is altered, resulting in changes in overall plasma concentrations; however, no substantial alterations in intrinsic clearance and concentrations of unbound drug.

In patients with renal impairment, protein binding is altered, resulting in changes in overall plasma concentrations, however, no substantial alterations in intrinsic clearance and concentrations of unbound drug.

A selective antagonist at alpha-1A and alpha-1B adrenoceptors in the prostate, prostatic capsule, prostatic urethra, and bladder neck.

THERAP CAT: In treatment of benign prostatic hypertrophy

5-[(2R)-2-[bis[2-[(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide

5-[(2R)-2-aminopropyl]-2-methoxybenzenesulfonamide

2-methoxy-5-[(2R)-2-[(2-phenoxyethyl)amino]propyl[benzenesulfonamide

2-methoxy-5-[(2R)-2-[[2-(2-methoxyphenoxy)ethyl]amino]propyl]benzenesulfonamide

For more Impurities (Complete) data for Tamsulosin (9 total), please visit the HSDB record page.