Absorption Metabolism and Excretion

Physostigmine and rivastigmine are tertiary amines that are rapidly absorbed from the gastrointestinal tract, as are tacrine, donepezil, and galanthamine, whereas quaternary ammonium compounds are poorly absorbed after oral administration. Nevertheless, quaternary ammonium compounds like neostigmine and pyridostig-mine are orally active if larger doses are employed. Only the quaternary ammonium inhibitors do not readily enter the CNS. Because of their high lipid solubility and low molecular weight, most of the organophos-phates are absorbed by all routes of administration; even percutaneous exposure can result in the absorption of sufficient drug to permit the accumulation of toxic levels of these compounds.

Edrophonium is partially metabolized to a glu-curonide conjugate in the liver. Some of this metabolite is excreted in bile. Carbamates undergo both nonenzy-matic and enzymatic hydrolysis, with enzymatic hydrolysis generally resulting from an interaction of the drug with the pseudo-ChE in plasma and liver. Organo-

phosphates are metabolized to inactive products by hy-drolytic enzymes in the plasma, kidney, liver, and lungs. In contrast, the organophosphate insecticide parathion requires metabolism (oxidative desulfuration) to become an effective insecticide.

Metabolites of the cholinesterase inhibitors and in some instances significant amounts of the parent compound are eliminated in the urine. Renal excretion is very important in the clearance of agents such as neostigmine, pyridostigmine, and edrophonium. This is demonstrated by a twofold to threefold increase in elimination half-lives for these drugs in anephric patients. Renal elimination is largely the result of glomerular filtration but probably also involves, at least in the case of quaternary amines, secretion via the renal cationic transport system.

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