Lipophilicity of 5-Hydroxymethyl Tolterodine, the Active Metabolite of Fesoterodine


Introduction and Objectives: Agents that can easily penetrate the blood-brain barrier (i.e., those with high lipophilicity at physiologic pH) may potentiate central nervous system (CNS) effects. The ability of antimuscarinic agents currently available for the treatment of overactive bladder (OAB) to cross the blood-brain barrier and cause cognitive impairment is of concern, particularly in elderly patients. Fesoterodine (FESO) is a new antimuscarinic agent for the treatment of OAB that is rapidly and extensively hydrolyzed by nonspecific esterases to its only active moiety, 5-hydroxymethyl tolterodine (5-HMT), which is chemically identical to the major active metabolite of tolterodine (Tubaro, A., and C. DeNunzio. [2004]. EAU Update Series 2: 161-169). It has been previously reported that tolterodine, a tertiary amine, has low lipophilicity and low CNS penetration (brain/blood ratio: 0.1 to 0.3 for radioactivity) in mice (Nilvebrant L. Rev Contemp Pharmacother. 2000;11:13-27). A comparison of the chemical structure of tolterodine and 5-HMT suggests that the latter is even less lipophilic owing to hydroxylation. Based on OECD Test Guideline (Nasal, A., et al. [2003]. Curr Med Chem 10: 381-426), the octanol:water distribution coefficient (logD) at pH 7.4 is commonly used to indicate lipophilicity of substances at the pH of blood plasma. The objective of this study was to determine the lipophilicity of 5-HMT compared with antimuscarinic agents currently used for treatment of OAB. 

Materials: The logD for 5-HMT was determined over a pH range of 2 to 12 at 20°C using the shake-flask method. Concentrations of 5-HMT were determined using high-performance liquid chromatography.

Results: 5-HMT demonstrated low lipophilicity at acid pH and higher lipophilicity at more basic pH, which would be expected for a compound with a pKa value of 9.28. In this study, the logD value for 5-HMT was 0.47 at pH 7.4.

LogD Values for 5-HMT as a Function of pH (Table 1). The lipophilicity of several antimuscarinic agents used for treatment of OAB has been previously reported. The results of this study are consistent with previous study results that reported the logD values of tolterodine and its active metabolite (also 5-HMT) to be 1.83 and 0.74, respectively (Nilvebrant, L. [2000]. Rev Contemp Pharmacother 11: 13-27). By comparison, the logD values of solifenacin and oxybutynin were 1.69 (Maniscalco, M., et al. [2006]. Clin Ther 28: 1247-1272) and > 3.3, respectively (Nilvebrant, L. [2000]. Rev Contemp Pharmacother 11: 13-27), indicating that these 2 compounds are more lipophilic than 5-HMT. Consistent with these data, the brain/plasma ratios of fesoterodine-related radioactivity were about 0.04 and 0.07 for the maximum observed concentration, and area under the curve, respectively, after single oral doses of [14C]fesoterodine given to mice (data on file: Pfizer Inc).

Conclusions: The logD value for 5-HMT at a pH of 7.4 was 0.47, which is consistent with previous reports. 5-HMT is more than 10 times less lipophilic than reported values for tolterodine, solifenacin, or oxybutynin, suggesting the least propensity of CNS effects with FESO.

KEYWORDS: Fesoterodine, OAB, antimuscarinic, lipophilicity, CNS adverse events