Pharmacokinetics and metabolism of zamifenacin in mouse, rat, dog and man

1. Zamifenacin was rapidly metabolized in vitro by liver microsomes from rat, dog, and man. 2. Zamifenacin exhibited extensive plasma protein binding with human plasma showing 20 and 10-fold higher binding that that in rat and dog respectively. 3. Following oral administration to animals, metabolic clearance resulted in decreased bioavailability due to first-pass metabolism in rat and mouse. Oral clearance in man was low as a result of increased metabolic stability and increased plasma protein binding compared with animals. 4. Metabolism was the major route of clearance of zamifenacin with the primary metabolic step resulting in opening of the methylenedioxy ring to yield the catechol. In man, this metabolite was excreted as the grucuronide conjugate, whereas in the animal species it was further metabolized by mono-methylation of the catechol.