Pharmacokinetics of the M1-agonist talsaclidine in mouse, rat, rabbit and monkey, and extrapolation to man.
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.
Leusch
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A
Department of Pharmacokinetics and Drug Metabolism, Boehringer Ingelheim Pharma KG, Biberach, Germany. andreas.leusch@bc.boehringer-ingelheim.com
Tröger
W
W
Greischel
A
A
Roth
W
W
D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002250:Carbon Radioisotopes; D005260:Female; D000882:Haplorhini; D006801:Humans; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D018721:Muscarinic Agonists / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011485:Protein Binding; D011812:Quinuclidines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011817:Rabbits; D051381:Rats; D013045:Species Specificity
D001798:Blood Proteins; D002250:Carbon Radioisotopes; D018721:Muscarinic Agonists; D011812:Quinuclidines; C079885:talsaclidine fumarate