Abstract
The in vivo characterization of drug-receptor binding facilitates integrated analysis of pharmacokinetics and pharmacodynamics of drugs. α1-Adrenergic antagonists and antimuscarinic agents are clinically useful in the treatment of lower urinary tract symptoms due to benign prostatic hypertrophy and overactive bladder (OAB). For anticholinergic therapy for OAB, side effects of dry mouth and cognitive impairment are concerns. Currently, novel agents have been developed to minimize these side effects. We have characterized in vivo muscarinic receptor (mAChR) binding of anticholinergic agents in the bladder, salivary gland and brain. Transdermal oxybutynin (Oxy) showed little long-lasting binding of mAChR in the submaxillary gland of rats after oral Oxy. Orally administered tolterodine and solifenacin bound mAChR in the bladder with a slower onset and longer duration than oral Oxy. In an autoradiographic study, there was a dose-dependent binding of mAChR in rat brain regions after intravenous injection of anticholinergic agents. The dose ratios for brain mAChR occupancy (RO50) to inhibition of carbachol-induced increase in intavesical pressure (ID50), which reflects in vivo bladder selectivity to brain, were significantly greater for solifenacin and tolterodine than Oxy. In a positron emission tomography study using conscious rhesus monkeys, brain mAChR occupancy was 40-60% at 1-4hr after oral Oxy at pharmacologically relevant doses. Our data shows that novel antimuscarinic agents are advantageous in the target organ selectivity of receptor occupancy after systemic administration. The in vivo receptor binding characteristics of these drugs were closely related to their pharmacological specificities.
