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• W2055149989 abstract "The aim of this study was to determine in vitro protein binding of tolterodine and its 5-hydroxymethyl (5-HM) and N-dealkylated metabolites in serum from humans and several animal species at concentrations similar to those obtained in clinical and preclinical studies. Binding of tolterodine and the two metabolites to human serum albumin and α1-acid glycoprotein (AAG) was also assessed, as was binding of tolterodine to red blood cells. Ex vivo protein binding of tolterodine and 5-HM was determined in serum samples from healthy volunteers treated with oral tolterodine 4 mg twice daily for 8 days. Tolterodine exhibited high protein binding in human serum; the unbound fraction (fu) was 3.7%. The unbound fraction of tolterodine in cat and dog serum (1.5 and 2.1%, respectively) was lower compared with human serum; fu was higher in the other species investigated (rat, 22%; mouse, 16–17%; rabbit, 39%). The unbound fraction of 5-HM was much higher in serum from humans (36%) and all animal species investigated (mouse, 72%; rabbit, 68%; cat, 32%; dog, 45%). Binding of N-dealkylated tolterodine to proteins in human serum was intermediate (fu 14%). AAG was the major binding protein for tolterodine and 5-HM, and the degree of binding increased with increasing concentration of the protein. The association constant of 5-HM for AAG was lower than that of tolterodine (1.3×105 M−1 versus 2.1×106 M−1). The blood:plasma tolterodine concentration ratio was 0.6 in both humans and dog; thus, a minor fraction of tolterodine was present in red blood cells compared with plasma (0.18 and 0.36, respectively). In the mouse, tolterodine was equally present in blood and plasma. In ex vivo samples, fu values for tolterodine (pH adjusted) varied between 1.6 and 4.9% (mean 2.8%), which could be explained by differences in AAG concentrations. There was good correlation between observed fu values for tolterodine and those predicted on the basis of AAG levels. Similar findings were observed for 5-HM. Copyright © 1999 John Wiley & Sons, Ltd." @default.
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• W2055149989 date "1999-03-01" @default.
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• W2055149989 title "Serum protein binding of tolterodine and its major metabolites in humans and several animal species" @default.
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• W2055149989 doi "https://doi.org/10.1002/(sici)1099-081x(199903)20:2<91::aid-bdd162>3.0.co;2-y" @default.
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