Pharmacokinetics of the M1-agonist talsaclidine in mouse, rat, rabbit and monkey, and extrapolation to man

Abstract

1. Talsaclidine is an M1-agonist under development for the treatment of Alzheimer's disease. The aim of the study was to investigate the absorption, distribution, metabolism and excretion (ADME) of single intravenous and oral doses of [14C]-talsaclidine in mouse, rat, rabbit and monkey. Previous data in humans showed that the drug was mainly excreted into the urine as the unchanged parent drug. The hypothesis was tested if animal data of drugs, which are mainly excreted renally, could be extrapolated to human. 2. The apparent volume of distribution at steady-state (V(ss)) was comparable in all animal species (2-5 l x kg(-1)) indicating an extensive distribution of the drug into tissues. The plasma protein binding was low and comparable in all species including man (< or = 7%). Elimination in terms of clearance was rapid-to-moderate depending on the species. The total plasma clearance (Cl) decreased in the order: mouse (128 ml x min(-1) x kg(-1))> rat (73.9) > monkey (10.6). Urinary excretion is the dominant route of excretion (> or = 86%). 3. A good correlation was achieved with human and animal data in allometric scaling of CI and V(ss). This confirms the hypothesis that renal filtration is scalable over the species and, given a comparable protein binding, animal data is predictive for man.

Dehydrogenases/Reductases for the Synthesis of Chiral Pharmaceutical Intermediates

“…(R)-3-Quinuclidinol (14) is an important chiral building block for the synthesis of various pharmaceuticals such as talsaclidine (15) and revatropate (16) [66,67] (Fig. (4A)).…”

Animal models of Alzheimer disease: historical pitfalls and a path forward

“…Enhanced cognitive performance in mice, improved short-term FDA approved for all disease memory and attention deficits induced by scopolamine in rats stages (AlzForum, 2014) (Dawson and Iversen, 1993) Galantamine Cholinesterase Improved short-term memory and attention deficits induced FDA approved for mild to by scopolamine in rats, reversed cognitive deficits in mice who moderate AD (AlzForum, 2014) had received CNS lesions (Sweeney et al, 1988(Sweeney et al, , 1989Chopin and Briley, 1992) Rivastigmine Cholinesterase Ameliorated aging-induced learning deficits and cholinergic FDA approved for mild to dysfunction in rats (Fisher et al, 2003) moderate AD (AlzForum, 2014) Tacrine Cholinesterase Improved short-term memory and attention deficits induced by FDA approved for mild to scopolamine in rats (Chopin and Briley, 1992) moderate AD (AlzForum, 2014) Phenserine Cholinesterase Significantly improved cognition in both rodents and canines Not effective (Haroutunian et al, 1997;Patel et al, 1998;Klein, 2007) (Becker and Greig, 2012) Ispronicline Cholinesterase Enhanced memory in mice and rats Not effective (Gatto et al, 2004;Lippiello et al, 2006) (Frolich et al, 2011) ABT-089 Cholinesterase Improved baseline and impaired cognitive function in rats Terminated (NIH, 2011) (Decker et al, 1997) Latrepirdine Cholinesterase Improved AD pathology and learning in mice and rats Not effective (Neale, 2010) (Lermontova et al, 2000;Perez et al, 2012;Steele and Gandy, 2013) Metrifonate Cholinesterase Improved acetylcholine levels in rats (Mori et al, 1995) Withdrawn from development (Lopez-Arrieta and EVP-6124 Cholinesterase Restored memory function in rats (Prickaerts et al, 2012) In clinical trials (Hilt et al, 2012) Talsaclidine M1 muscarinic Improved cognitive outcome in mouse, rabbit, and lemur Undesirable side effects receptor models of AD (Leusch et al, 2000) (Wienrich et al, 2001) AF-102B M1 muscarinic Improved cognitive outcome in mouse, rabbit, and lemur Undesirable side effects receptor models of AD (Fisher et al, 2003) …”

Structural analysis of enzymes used for bioindustry and bioremediation

“…One of the chiral alcohols, (R)-3-quinuclidinol, is useful as a building block of various pharmaceuticals, including talsaclidine, 10,11) which is a nonselective muscarinic acetylcholine receptor agonist and is intended for muscarinic substitution therapy in patients with Alzheimer's disease. The production of (R)-3-quinuclidinol has been achieved by chemical and biochemical methods based on the optical resolution of a racemic mixture.…”