Prediction of .ALPHA.1-Adrenoceptor Occupancy in the Human Prostate from Plasma Concentrations of Silodosin, Tamsulosin and Terazosin to Treat Urinary Obstruction in Benign Prostatic Hyperplasia

Abstract

The prediction of optimal dosage regimens in humans is important for clinical studies in the development of novel drugs and also for the risk assessment of adverse effects. For this purpose, it may be useful to estimate receptor occupancy for drugs in human target organs using drug-receptor-binding parameters and pharmacokinetic parameters. Several investigators, based on the receptor occupancy theory, have previously assessed the rational dosage, extent, and duration of pharmacologic effects, and the adverse effects of antagonists for histamine receptors, b-adrenoceptors, dopamine receptors, and muscarinic receptors in humans.

Combined medical treatment using dutasteride and tamsulosin for lower urinary tract symptoms suggestive of benign prostatic hyperplasia

“…The lowest percentage of occupancy 24 h later was 44%. Since > 40% receptor blockade persists to 24 h, beneficial clinical effects would be expected with oncedaily administration of an oral dose of tamsulosin (0.45 mmol) [28].…”

Safety and Pharmacokinetic Studies of Silodosin, a New .ALPHA.1A-Adrenoceptor Selective Antagonist, in Healthy Chinese Male Subjects

“…In a study with Chinese hamster ovary cells expressing three human a 1 -AR subtypes, the selectivity of silodosin to the a 1A -AR subtype was 38 times higher than that of tamsulosin hydrochloride, 3) indicating a specificity to the lower urinary tract (LUT) where a 1A -AR is the predominant subtype. 4,5) In comparative studies with rat and dog models, silodosin produced more favorable uroselectivity as compared to tamsulosin or prazosin.6,7) Silodosin improves not only urinary dysfunction but also irritative symptoms associated with BPH. 8,9) Silodosin was approved in Japan for treating BPH (4 mg, bid) in January 2006, and was approved by the Food and Drug Administration (FDA, U.S.A.) for the same indication (8 mg, once a day (qd)) in October 2008.…”

“…In a study with Chinese hamster ovary cells expressing three human a 1 -AR subtypes, the selectivity of silodosin to the a 1A -AR subtype was 38 times higher than that of tamsulosin hydrochloride, 3) indicating a specificity to the lower urinary tract (LUT) where a 1A -AR is the predominant subtype. 4,5) In comparative studies with rat and dog models, silodosin produced more favorable uroselectivity as compared to tamsulosin or prazosin.…”

Effects of the Selective α1A-Adrenoceptor Antagonist Silodosin on ECGs of Healthy Men in a Randomized, Double-Blind, Placebo- and Moxifloxacin-Controlled Study

“… 10 This concentration is >2,000 times the maximum plasma concentration (_4 nmol/l) of unbound silodosin in subjects who received a single therapeutic dose (8 mg; 16.1 µmol) of silodosin. 11 …”

“…10 This concentration is >2,000 times the maximum plasma concentration (~4 nmol/l) of unbound silodosin in subjects who received a single therapeutic dose (8 mg; 16.1 μmol) of silodosin. 11 In accordance with the International Conference on Harmonisation E14 guidance, we conducted a thorough doubleblind, placebo-controlled study in healthy men to evaluate the effects of silodosin on QT prolongation and other ECG para meters. The primary objective was to determine whether therapeutic or supratherapeutic doses of silodosin cause QTc prolongation.…”