A comprehensive non‐clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive bladder

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• This study provides antimuscarinic agents for overactive bladder (OAB) display variable association with side effects mediated by the central nervous system (CNS), which may be of particular concern in the elderly.• Adverse effects on CNS functioning are related to muscarinic receptor subtype selectivity and the ability of the agent to cross the blood-brain barrier, where P-gp plays a role in limiting permeability. WHAT THIS STUDY ADDS• This study provides a parallel investigation of CNS penetration of antimuscarinic OAB agents in vivo and assessment of physical properties and permeability in cell monolayers in vitro.• It adds further understanding of the roles of passive transcellular permeability and P-gp in determining CNS penetration of antimuscarinic OAB agents.• It also enables a comparison of CNS side-effect profiles of OAB agents with preclinical CNS penetration data. AIMSTo assess and compare the mechanisms of central nervous system (CNS) penetration of antimuscarinic overactive bladder (OAB) agents. METHODSPhysical properties were computed or compiled from the literature. Rats were administered 5-hydroxymethyl tolterodine (HMT), darifenacin, oxybutynin, solifenacin, tolterodine or trospium subcutaneously. At 1 h postdose, plasma, brain and cerebrospinal fluid (CSF) concentrations were determined using LC-MS/MS assays. Brain and plasma protein binding were determined in vitro. Permeability in the presence and absence of the efflux transporter P-glycoprotein (P-gp) was assessed in RRCK and MDCK-MDR1 transwell assays. RESULTSOxybutynin displayed extensive CNS penetration, with brain : plasma ratios (B : P), unbound brain : unbound plasma ratios (Kp,free) and CSF : free plasma ratios each >1. Tolterodine (B : P = 2.95, Kp,free = 0.23 and CSF : free plasma = 0.16) and solifenacin (B : P = 3.04, Kp,free = 0.28 and CSF : free plasma = 1.41) showed significant CNS penetration but with some restriction from CNS as indicated by Kp,free values significantly <1. 5-HMT, darifenacin and trospium displayed much lower B : P (0.03-0.16), Kp,free (0.01-0.04) and CSF : free plasma (0.004-0.06), consistent with poor CNS penetration. Permeability in RRCK cells was low for trospium (0.63 ¥ 10 -6 cm s ), moderate for 5-HMT (11.7 ¥ 10 -6 cm s ) and high for darifenacin, solifenacin, tolterodine and oxybutynin (21.5-38.2 ¥ 10 -6 cm s -1). In MDCK-MDR1 cells 5-HMT, darifenacin and trospium, were P-gp substrates, whereas oxybutynin, solifenacin and tolterodine were not P-gp substrates. CONCLUSIONSBrain penetration was low for antimuscarinics that are P-gp substrates (5-HMT, darifenacin and trospium), and significant for those that are not P-gp substrates (oxybutynin, solifenacin and tolterodine). CNS adverse events reported in randomized controlled clinical trials show general alignment with the preclinical data described in this study.

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

“…Thus, it can be extrapolated that in EM subjects, the metabolite contributes the lion's share of the activity, while in PM subjects the parent drug would be the major contributor. Furthermore, it was shown in animal studies that 5-hydroxymethyltolterodine has a lower capability to penetrate the brain (as assessed using K p,uu values; Callegari et al, 2011), thus it could be proposed that the metabolite would have lower propensity to cause side effects caused by antimuscarinic activity in the brain, such as memory impairment. The lack of an impact of CYP2D6 on the metabolism of 5-hydroxymethyltolterodine served as a rationale for the development of fesoterodine, an ester prodrug of the metabolite (Malhotra et al, 2009).…”

Wer ältere Patienten urologisch behandeln will, muss umdenken

“…Octanol/H O-Verteilungskoe zient LogD: Substanzen mit guter Löslichkeit in Alkohol (Octanol) verhalten sich lipophil (ZNS[Zentralnervensystem]-gängig) und nden sich oberhalb der Abszisse, hydrohpile Substanzen mit guter Löslichkeit in Wasser nden sich unterhalb der Abszisse (nicht ZNS-gängig)[17] …”

Delirium following fesoterodine treatment for urgency incontinence in an 89-year old man

“…5-HMT crosses the blood-brain barrier (BBB), but is actively transported out of the CNS by the P-glycoprotein (P-gp), which leads to a non-significant concentration in the CNS in an vivo animal model. 3 From the data available from clinical trials, 4,5 some authors have stated that fesoterodine doesn't cause cognitive impairment in elderly patients. Its effect on attention, memory, and executive function was similar to placebo in a double-blind, double-dummy, crossover study on 20 healthy elderly patients aged between 65 and 84 years old.…”