Assay analysis of tamsulosin and terazosin pharmacokinetics
α1-Adrenoceptor antagonists have long been used in the treatment of arterial hypertension. Recently, they have also been introduced for the symptomatic treatment of benign prostatic hyperplasia. Receptor cloning and pharmacological analysis have identified the existence of at least three α1-adrenoceptor subtypes which are designated α1A (formerly α1c ), α1B and α1D (formerly α1a/d ). Since human prostate predominantly expresses α1A-adrenoceptors at the mRNA and protein level, it has been postulated that selective binding to α1A-adrenoceptors may be sufficient to yield full therapeutic efficacy in benign prostatic hyperplasia with perhaps less side effects related to vasodilation. On the other hand, it has been reported that some α1A-selective antagonists only poorly inhibit contraction of human prostate in vitro; it was proposed that an additional subtype designated α1L may be involved in prostatic contraction. More recent studies, however, have found that several compounds which have higher affinity for α1A- than for the putative α1L-adrenoceptors in standard binding assays using membrane preparations at room temperature also have low affinity for α1A-adrenoceptors when assayed in intact cells at 37° C; they have suggested that the α1L subtype may be a conformational state of the α1A-adrenoceptor. Thus, the overall evidence suggests that indeed the α1A-adrenoceptor may be the main mediator of human prostatic contraction.
Most clinically used α1-adrenoceptor antagonists, e.g. terazosin, were originally developed for the treatment of arterial hypertension and do not discriminate α1-adrenoceptor subtypes. In contrast, the novel antagonist, tamsulosin, was specifically developed for the symptomatic treatment of benign prostatic hyperplasia and has about 15-fold selectivity for α1A- over α1B-adrenoceptors with intermediate affinity for α1D-adrenoceptors. Interestingly placebo-controlled clinical trials with terazosin have reported larger incidences of unwanted side effects than trials with tamsulosin but a direct comparison has not been performed.
The present study was designed to gain further insight into a potential role of α1-adrenoceptor subtype selectivity in the action of tamsulosin and terazosin. This was done by a pharmacokinetic analysis of receptor binding following a single, oral dose of tamsulosin (0.4 mg) and terazosin (5 mg) in a placebo-controlled, single-blind, randomized, three-way cross-over study. For this purpose we have developed a new radioreceptor assay using cloned human α1-adrenoceptor subtypes stably expressed in rat-1 fibroblasts. With this assay we have assessed binding to each of the three subtypes at 1, 3, 5, 7, 10 and 23.5 h following drug intake. Specific analysis of tamsulosin and terazosin plasma concentrations by specific h.p.l.c. analysis was performed in comparison.
The study protocol was approved by the ethics committee at the University of Essen Medical School. Ten healthy male subjects (median age: 26.5 years, range: 22–36 years) participated after having given informed written consent. Each subject completed 3 study days during which they received in a single-blinded, randomized cross-over manner 1 tablet of 5 mg terazosin (purchased as Flotrin® from a German pharmacy), 1 capsule of 0.4 mg tamsulosin modified release formulation (Omnic®, provided by Yamanouchi Europe B.V., Leiderdorp, Netherlands), or 1 capsule of placebo matching the tamsulosin capsule. Study days were at least 7 days apart to secure sufficient drug washout.
On each study day the subjects reported to the laboratory at 07.00 h after an overnight fast. An indwelling catheter was placed into a forearm vein for blood withdrawals. The subjects remained in the supine position until after the last blood withdrawal 24 h after drug ingestion. Blood samples were taken 2 h before and 1, 3, 5, 7, 10 and 23.5 h after drug intake. The blood samples were collected into EDTA-coated tubes to prevent coagulation. They were stored on ice immediately. Plasma samples were generated by centrifugation and stored at −20° C until analysis, i.e. up to 4 months. Each blood sample was used for h.p.l.c. and radioreceptor analysis. A light snack was allowed after the 7 h blood withdrawal and a pizza or pasta dish after the 10 h withdrawal. While no other food was given until after the last blood withdrawal, drinking of water was allowed ad libitum.
Filed under: Clinical Pharmacology