Absorption, metabolism, and disposition of [14C]SDZ ENA 713, an acetylcholinesterase inhibitor, in minipigs following oral, intravenous, and dermal administration.
OBJECTIVE
SDZ ENA 713 (rivastigmine) is an acetylcholinesterase inhibitor intended for therapeutic use in Alzheimer's disease. The present study compared the pharmacokinetics of [14C]SDZ ENA 713 after intravenous, oral, and dermal administration to male minipigs, and also examined the effects of dose level and skin abrasion on transdermal absorption.


METHODS
Four groups of 3 minipigs each received a single intravenous (0.1 mg/kg), single oral (1.0 mg/kg), or topical doses of 18 mg or 54 mg of [14C]SDZ ENA 713. Topical doses were administered as dermal patches on two occasions 10 days apart. On Study Day 1, test patches were applied to a virgin skin site. Placebo patches were applied to a separate skin site and were replaced daily during Days 1-10. On Study Day 11, test patches were applied to the site on which the placebo patches had been previously applied. After each dose, serial blood and quantitative urine and feces were collected at designated intervals for 7 days. Concentrations of radioactivity, parent drug, and metabolite ZNS 114-666 were measured in whole blood. Radioactivity was also determined in excreta, skin application sites (at study termination), and on used dermal patches (at 24 hr after application).


RESULTS
Oral doses of [14C]SDZ ENA 713 were rapidly (tmax = 0.83 hr) and efficiently (ca. 93%) absorbed, although the bioavailability of the parent drug was low, ca. 0.5%, apparently due to extensive first-pass metabolism. Radioactivity was excreted mainly in the urine (approximately 90%) with a half-life of 56 hr, slightly longer than that observed after an intravenous dose, 46 hr. After dermal administration of [14C]SDZ ENA 713 to a virgin skin site, absorption was 8% at both dose levels investigated. Following daily application of placebo patches for 10 days, absorption from a [14C]SDZ ENA 713 dermal patch increased by approximately twofold, 17% and 19% of the 18 mg and 54 mg doses, respectively. The increase is possibly due to hydration or abrasion of the skin as a result of repeated application and removal of the adhesive patches. Whereas total absorption from the dermal dose was smaller than that from the oral dose, essentially all of the absorbed drug via the dermal route reached the systemic circulation intact, thus yielding a SDZ ENA 713 bioavailability 20-40 times greater than that of the oral dose. Metabolite ZNS 114-666 was rapidly formed and accounted for <4% of total drug-related material in the systemic circulation.


CONCLUSIONS
Dermal administration in minipigs provided a markedly greater bioavailability of SDZ ENA 713 than the oral route. The extent of absorption was independent of dose within the range tested, and appeared to be enhanced by hydration or abrasion of the skin application site.
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Department of Drug Metabolism and Pharmacokinetics, Preclinical Safety, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, USA. francis.tse@pharma.novartis.com
Laplanche
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D000279:Administration, Cutaneous; D000284:Administration, Oral; D000818:Animals; D002219:Carbamates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D048448:Phenylcarbamates; D000068836:Rivastigmine; D013552:Swine; D013556:Swine, Miniature
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D048448:Phenylcarbamates; D000068836:Rivastigmine