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Orally administered reserpine is readily absorbed from the GI tract. During this process at least a portion of the drug is metabolized by the intestinal mucosa and then presumably is acted upon by serum esterases. Methylreserpate and trimethoxybenzoic acid are the primary metabolites which result from the hydrolytic cleavage of reserpine. Since most of the blood leaving the GI tract passes through the liver via the portal vein, hepatic metabolism would also be expected to reduce reserpine levels in the blood. The relative contributions of serum esterases versus hepatic metabolism in the biotransformation of reserpine in vivo are not known. However, very little unmetabolized reserpine is eventually eliminated in the urine. In the liver, it is quite likely that both microsomal oxidative and hydrolytic enzymes contribute to the metabolism of reserpine. It seems that microsomal oxidation (such as the demethylation of the 4-methoxy group on the TMBA moiety) must precede hydrolysis since inhibition of demethylation markedly reduces the rate of hydrolysis. In addition to oxidation and hydrolysis, conjugative reactions also must occur in liver or extrahepatic tissues since both glucuronide and sulfate conjugates of TMBA have been identified. Some reserpine molecules do seem to escape metabolism, however, since significant amounts of intact reserpine have been found in fecal samples taken from both experimental animals and human beings after either oral or parenteral drug administration. Presumably reserpine is transported from the blood via the biliary tree into the small intestine where it is either reabsorbed or eliminated in the feces. Pulmonary elimination of CO2 produced after complete oxidation of the 4-methoxy group of TMBA has also been shown to occur both in vivo and in vitro. The following may serve as a model for the relationship between the subcellular distribution of reserpine and its site of action. After a single intravenous injection most of the reserpine, probably loosely bound to plasma albumin, is distributed to tissues on the basis of their blood flow. Because of its lipophilic properties, reserpine would easily penetrate cell membranes and then bind possibly electrostatically to intracellular membrane components, particularly those rich in phospholipids. Much of the circulating reserpine would then either be metabolized or be taken up by the lipid depots of the body, leading to a rapid redistribution of the reversibly bound reserpine from the tissues. During this time a relatively small fraction of the total reserpine administered by injection would become associated with monoaminergic granular membranes in a more specific and irreversible manner. This would result in a persistent, nonstoichiometric inhibition of monoamine uptake. Such a small specific binding would not be detectable for at least 18 hr after reserpine administration, i.e., until most of the reversibly bound alkaloid had been metabolized and/or excreted...