Disposition of SDZ ENA 713, an acetylcholinesterase inhibitor, in the rabbit.
The disposition of SDZ ENA 713, indicated for the treatment of Alzheimer's disease, was studied in non-pregnant, pregnant, and lactating New Zealand white rabbits. 3H-SDZ ENA 713 was administered as single oral or intravenous dose (1.09 mg kg-1) and as multiple oral doses (1.09 mg kg-1) daily for 7 days. Serial blood and milk samples, selected tissues and excreta samples were collected. Radioactivity was determined in all biological samples by liquid scintillation counting. Concentrations of unchanged SDZ ENA 713 and its phenolic metabolite, ZNS 114-666, were measured by GC-MS. Pharmacokinetic parameters were determined by model independent methods. The rate and onset of absorption were rapid (tmax 1.3 +/- 0.58 h) and the extent of absorption was essentially complete. Concentrations of SDZ ENA 713 were below the limit of quantification (0.98 ng mL-1) after oral administration. Following intravenous administration, SDZ ENA 713 was extensively distributed (Vss = 3.1 L kg-1) and rapidly cleared (Cl = 2.7 L h-1 kg-1). The radioactivity was primarily excreted via the kidneys (86% of dose). In pregnant rabbits receiving multiple oral doses, the fetus to placentae tissue ratio of radioactivity averaged 0.5. Passage of radioactivity from blood into milk was rapid (tmax = 2 h) and the milk:blood AUC ratio of radioactivity averaged 1.5. No unchanged SDZ ENA 713 was detected in the milk samples; however, there were measurable concentrations of the phenolic metabolite (Cmax = 82.9 ng mL-1). The milk to blood ratio of the phenolic metabolite averaged 2.3. In conclusion, SDZ ENA 713 underwent extensive presystemic metabolism following oral administration. There was moderate transfer of drug-related materials across the placenta. Projecting the rabbit data to humans, it is suggested that nursing neonates would not be exposed to unchanged SDZ ENA 713 following oral doses to nursing mothers.
Department of Drug Metabolism and Pharmacokinetics, Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
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D000818:Animals; D002219:Carbamates / Q000493:pharmacokinetics*; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D008892:Milk / Q000378:metabolism; D048448:Phenylcarbamates; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011817:Rabbits; D000068836:Rivastigmine; D014018:Tissue Distribution
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D048448:Phenylcarbamates; D000068836:Rivastigmine