α1-Adrenoceptors and muscarinic receptors in voiding function - binding characteristics of therapeutic agents in relation to the pharmacokinetics

Abstract

In vivo and ex vivo binding of α(1)-adrenoceptor and muscarinic receptors involved in voiding function is reviewed with therapeutic agents (α(1)-adrenoceptor antagonists: prazosin, tamsulosin and silodosin; and muscarinic receptor antagonists: oxybutynin, tolterodine, solifenacin, propiverine, imiafenacin and darifenacin) in lower urinary tract symptoms. This approach allows estimation of the inhibition of a well-characterized selective (standard) radioligand by unlabelled potential drugs or direct measurement of the distribution and receptor binding of a standard radioligand or radiolabelled form of a novel drug. In fact, these studies could be conducted in various tissues from animals pretreated with radioligands and/or unlabelled novel drugs, by conventional radioligand binding assay, radioactivity measurement, autoradiography and positron emission tomography. In vivo and ex vivo receptor binding with α(1)-adrenoceptor antagonists and muscarinic receptor antagonists have been proved to be useful in predicting the potency, organ selectivity and duration of action of drugs in relation to their pharmacokinetics. Such evaluations of drug-receptor binding reveal that adverse effects could be avoided by the use of new α(1)-adrenoceptor antagonists and muscarinic receptor antagonists for the treatment of lower urinary tract symptoms. Thus, the comparative analysis of α(1)-adrenoceptor and muscarinic receptor binding characteristics in the lower urinary tract and other tissues after systemic administration of therapeutic agents allows the rationale for their pharmacological characteristics from the integrated viewpoint of pharmacokinetics and pharmacodynamics. The current review emphasizes the usefulness of in vivo and ex vivo receptor binding in the discovery and development of novel drugs for the treatment of not only urinary dysfunction but also other disorders.

Figure 1

Schematic representation of in vivo drug–receptor binding in relation to pharmacokinetics and pharmacodynamics. This modified figure is reproduced from reference [23] with permission

Figure 2

Schematic representation of in vivo drug–receptor binding characteristics in target and nontarget tissues, and physiological, pharmacokinetic and pharmacodynamic factors affecting in vivo drug–receptor binding. BBB, blood–brain barrier

Figure 3

In vivo specific binding of [³H]prazosin, [³H]tamsulosin and [³H]silodosin in the prostate, submaxillary gland, aorta and spleen of rats after the intravenous injection. *P < 0.05, **P < 0.01, ***P < 0.001 significantly different from the value of [³H]prazosin

Figure 4

Muscarinic receptor binding (increase in the dissociation constant, K_d, for specific [³H]NMS binding) in the bladder, submaxillary gland, heart, colon, lung and brain of rats 1–12 h after the oral administration of imidafenacin [0.25 (A), 0.50 (B) or 2.0 mg kg⁻¹ (C)]. Control (); 1 h (); 3 h (); 6 h (); 9 h (); 12 h ()

Figure 5

(A) Typical positron emission tomography images fused with computed tomography images in the brain of rats injected intravenously with [¹¹C](+)3-MPB. The colour coding represents linear pseudocolouring of phosphor imager signal units (% of maximum). This modified figure was reproduced from reference [70] with permission

Figure 6

(A) Typical autoradiographic images in the brain of rats injected intravenously with [¹¹C](+)3-MPB. (B) Effects of different doses of oxybutynin (0.1–1.0 mg kg⁻¹), darifenacin (0.1–1.0 mg kg⁻¹) and imidafenacin (0.01–0.1 mg kg⁻¹) on autoradiographic images of [¹¹C](+)3-MPB in the rat brain. The colour coding represents linear pseudocolouring of phosphor imager signal units (% of maximum). This modified figure was reproduced from reference [70] with permission