Pharmacokinetics of tolterodine, a muscarinic receptor antagonist, in mouse, rat and dog. Interspecies relationship comparing with human pharmacokinetics.
Tolterodine ((R)-N,N-diisopropyl-3-(2-hydroxy-5-methyl-phenyl)-3-phenylpropanamine, CAS 124937-51-5) is an antimuscarinic agent developed specifically for the treatment of the overactive bladder. In this study, the pharmacokinetics of tolterodine were investigated in the mouse, rat and dog, following which allometric scaling was performed to predict oral pharmacokinetics in man. The intestinal absorption of tolterodine after oral dosing was almost complete in all three species, with peak serum concentrations observed within 1 hour post-dose. Bioavailability varied between 2-20% in rodents and 58-63% in the dog. A high volume of distribution in all three species was consistent with extravascular distribution. Tolterodine was extensively metabolised in all the animal models, but the profile of metabolism differed in the rat compared to the mouse and dog, the latter having similar metabolism routes as man. Limitation of metabolism capacity caused a non-linear increase of tolterodine concentrations with dose (repeat-dose study in the mouse), and changed the relative metabolite concentration pattern. The results suggest that the hydroxylation of tolterodine is a high affinity, low capacity pathway, while N-dealkylation follows a low affinity, high capacity pathway. The elimination of tolterodine from serum was rapid, with a half-life of less than 2 h in all species. A very high clearance in the mouse and rat (10-15 l/h.kg), and in the dog (1.4 l/h.kg), indicated additional non-metabolic clearance mechanisms for tolterodine (shown to be attributed to biliary excretion). Urinary excretion of compound-related radioactive substance was around 15%, 45% and 50%, respectively, in the rat, mouse and dog. Allometric scaling allowed a good prediction of clearance and volume of distribution to be extrapolated for comparison with tolterodine pharmacokinetics in man. In conclusion, the pharmacokinetics of tolterodine are similar in the mouse and dog, and correlate with that in man. Although the rat has a different metabolic profile, clearance fits into the allometric relationship between species, enabling prediction of total clearance of tolterodine in man from preclinical data.
Påhlman
I
I
Department of Drug Metabolism Research, Pharmacia AB, Stockholm, Sweden. ingrid.pahlman@astrazeneca.com
Kankaanranta
S
S
Palmér
L
L
D000818:Animals; D001559:Benzhydryl Compounds / Q000493:pharmacokinetics* / Q000652:urine; D001646:Bile / Q000378:metabolism; D003408:Cresols / Q000493:pharmacokinetics* / Q000652:urine; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005333:Fetus / Q000378:metabolism; D007275:Injections, Intravenous; D051379:Mice; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics* / Q000652:urine; D010665:Phenylpropanolamine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014018:Tissue Distribution; D000068737:Tolterodine Tartrate
D001559:Benzhydryl Compounds; D003408:Cresols; D018727:Muscarinic Antagonists; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate