Functional Uroselectivity

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The efficacy-tolerability profile of tamsulosin in patients with benign prostatic hyperplasia (BPH) is assumed to be associated both with the a1-adrenoceptor selectivity profile of the drug and a small peak : trough ratio in the plasma pharmacokinetic (PK) profile. Tamsulosin is highly bound to plasma proteins, notably a1-acid glycoprotein (AGP). This protein is a high-affinity binding protein and AGP plasma concentration was found to influence the therapeutic (unbound) plasma concentrations for high-AGP-binding drugs. WHAT THIS STUDY ADDS• The study actually assessed unbound tamsulosin concentrations in both blood plasma and prostate tissue and reported that the unbound tamsulosin concentrations after multiple dosing in men with BPH, were much higher in prostate than in blood plasma. The assumption is put forward that differential free drug concentrations in prostate and blood plasma may contribute to the relative 'uroselectivity' of tamsulosin. AIMThe aim of this small patient study was to investigate tamsulosin concentrations in prostate and plasma samples in order to identify potential differences in the pharmacokinetics (PK) in plasma and prostate contributing to its pharmacodynamic activity profile in patients. METHODSForty-one patients with benign prostatic hyperplasia (BPH) scheduled for open prostatectomy were given tamsulosin 0.4 mg for 6-21 days in order to reach steady-state PK. Patients were randomized over four groups to allow collection of plasma and tissue samples at different time points after last dose administration. Samples were collected during surgery and assayed for tamsulosin HCl. The free fraction (fu) of tamsulosin was determined by ultracentrifugation of plasma and prostate tissue spiked with 14 C-tamsulosin. RESULTSCmax in plasma at 4.4 h for total tamsulosin was 15.2 ng ml -1 and AUC(0,24 h) was 282 ng ml -1 h, while for prostate Cmax at 11.4 h post-dose was 5.4 ng ml -1 and AUC(0,24 h) was 120 ng ml -1 h. AUC(0,24 h) for total tamsulosin in prostate was 43% of the plasma AUC(0,24 h). fu was 0.4 % for plasma and 59.1% for prostate. Therefore calculated on unbound tamsulosin, a ratio of 63 resulted for prostate vs. plasma Cmax concentrations. CONCLUSIONSThese data indicate that in patients with confirmed BPH the amount of tamsulosin freely available in the target tissue (prostate) is much higher than in plasma.

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“…Uroselectivity, as it pertains to α 1 ‐adrenoceptor antagonists used in BPH, has been defined in different ways in the literature [33–35]:…”

Section: Discussionmentioning

confidence: 99%

“…Functional/Physiological uroselectivity of an α 1 ‐adrenoceptor blocker refers to a preferential effect on urethral pressure vs . arterial blood pressure, by non‐availability of human data established in animal models [34, 35].…”

Section: Discussionmentioning

confidence: 99%

Tamsulosin shows a higher unbound drug fraction in human prostate than in plasma: a basis for uroselectivity?

Korstanje

Krauwinkel

Doesum-Wolters

2011

Brit J Clinical Pharma

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“…Structural differences and well-defined mechanisms of action of AR antagonists might account for substantial differences in cases of IFIS. Alfuzosin has been reported to show selectivity only for the a1A subtype [37] , and act as a pure competitive antagonist in human prostatic smooth muscle [38] , as do terazosin [34] and prazosin [39] . Similar to prazosin [40] , alfuzosin behaves as a competitive antagonist in human iris smooth muscle.…”

Section: Discussionmentioning

confidence: 99%

Is sulfonamide group of tamsulosin main factor in the pathophysiology of floppy iris syndrome?

Ürkmez¹

2018

Haydarpasa Numune Med J

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Intraoperative floppy iris syndrome (IFIS) was first described by Chang et al. in 2005 in using α-blockers. Tamsulosin a selective α-(a) adrenergic receptor (AR) antagonist is a commonly prescribed drug for benign hyperplasia of the prostate (BPH), and it has been shown to have the strongest association with IFIS. Other drugs that predispose to IFIS include alfuzosin, doxazosin, terazosin, finasteride, labetalol, mianserin, chlorpromazine, donepezil and other antipsychotic agents. In literature reviews, the pathophysiological evaluation of IFIS has not yielded clear results. In the present study, we examined this pathophysiological mechanism from a different perspective and somewhat hypothetically analyzed the chemical composition of these drugs. We analyzed their chemical formulas and pharmacological effects in combination. We compared tamsulosin with other IFIS-inducing α-blockers and propose that its sulfonamide group might be a causative factor.

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“…10 The relatively low selectivity for the α1B adrenergic receptor, which is mainly involved in the regulation of blood pressure, allows silodosin to have minimal effects on the cardiovascular system. 10 , 11 , 12 In a randomized controlled study to evaluate the noninferiority of silodosin to tamsulosin, silodosin caused no significant change in systolic BP, diastolic BP, and heart rate from baseline; in contrast, tamsulosin produced a statistically significant decrease in systolic BP. 13 Based on this safety profile, we could assume that silodosin has advantages in LUTS patients with HTN.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of silodosin in the treatment of lower urinary tract symptoms in elderly men taking antihypertensive medications

Choi

Cho

Lee

et al. 2017

Prostate International

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BackgroundBoth hypertension and lower urinary tract symptoms (LUTS) are common conditions in the elderly population. This study investigated the efficacy and safety of silodosin in the treatment of LUTS in elderly men who were taking antihypertensive medications.MethodsThis is an observational study which collected the medical records of patients who started silodosin medication for their LUTS between April 2015 and December 2015. Inclusion criteria were age ≥ 65 years, currently taking antihypertensive medication, and International Prostate Symptom Score (IPSS) ≥ 8. Pretreatment evaluation included IPSS, Male Sexual Health Questionnaire, systemic symptoms, blood pressure, and uroflowmetry. Post-treatment evaluation was performed 3 months after the initial administration of silodosin medication.ResultsMean age of the total 48 patients was 70.7 ± 5.2 years. Thirty-two (66.7%) patients who continued silodosin single treatment showed a significant decrease in IPSS Quality of life scores (4.2 ± 1.1 vs. 3.0 ± 1.6, P = 0.001) and an increase in the maximum flow rate (10.7 ± 6.0 mL/s vs. 14.0 ± 4.5 mL/s, P = 0.001). Blood pressures did not change, and none of the patients needed to adjust their antihypertensive medication. New development of orthostatic hypotension was observed in one (2.5%) patient. Among the six patients who had orthostatic hypotension before silodosin treatment, none of the patients showed symptom aggravation. Ejaculatory dysfunction that required discontinuation of silodosin medication developed in only one (2.5%) patient.ConclusionSilodosin is an effective and safe agent in elderly men who are taking antihypertensive medications. Silodosin has an advantage in the treatment of LUTS in this population, even if the patients have orthostatic hypotension before treatment.

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Functional Uroselectivity

Cited by 14 publications

References 14 publications

Tamsulosin shows a higher unbound drug fraction in human prostate than in plasma: a basis for uroselectivity?

Tamsulosin shows a higher unbound drug fraction in human prostate than in plasma: a basis for uroselectivity?

Is sulfonamide group of tamsulosin main factor in the pathophysiology of floppy iris syndrome?

Efficacy and safety of silodosin in the treatment of lower urinary tract symptoms in elderly men taking antihypertensive medications

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