Brain distribution and muscarinic receptor occupancy of an active metabolite of fesoterodine in rats

Several large-scale clinical trials have shown that long-term use of antimuscarinic agents for overactive bladder treatment increases the risk of dementia and that this risk varies between agents. Fesoterodine, an overactive bladder antimuscarinic, reportedly has no significant effect on cognitive function. Differences in the brain distribution of antimuscarinic agents and blockade of muscarinic receptors could be the reasons for the differences in central side effects among antimuscarinics. In this study, we assessed the brain distribution of antimuscarinic agents and muscarinic receptor occupancy using brain microdialysis and in vivo receptor-binding analysis in rats. The test drugs were 5-hydroxymethyl tolterodine (5-HMT), an active metabolite of fesoterodine, oxybutynin, and trihexyphenidyl, a central antimuscarinic agent. The brain/plasma unbound concentration ratio at steady state (K_puu) of 5-HMT was much lower than that of oxybutynin and trihexyphenidyl, indicating very low 5-HMT distribution in the brain. The muscarinic receptor occupancy in the rat brain at clinical plasma concentrations of 5-HMT was rarely observed, whereas the occupancy by oxybutynin and trihexyphenidyl was 20% and 67%, respectively. The brain muscarinic receptor occupancy, reconstituted using K_puu values and muscarinic receptor affinity retrieved from literature, revealed a significant correlation between the calculated and measured values. These results indicate that 5-HMT has low brain distribution and muscarinic receptor occupancy, which might be the reasons for the insignificant effect of fesoterodine on cognitive function. SIGNIFICANCE STATEMENT: This study reports that 5-hydroxymethyl tolterodine, the active metabolite of fesoterodine, has much lower brain distribution and muscarinic receptor occupancy compared with oxybutynin and trihexyphenidyl based on brain microdialysis and in vivo receptor-binding analysis with unlabeled muscarinic tracer in rats. The low brain distribution and muscarinic receptor occupancy of 5-hydroxymethyl tolterodine might be the reasons for the insignificant effect of fesoterodine on cognitive function.