All TCAs share similar pharmacokinetic properties. They are highly lipophilic and readily cross the blood-brain barrier, and peak plasma levels occur between 2 and 6 h after ingestion at therapeutic doses. Gastrointestinal absorption can be prolonged because of their antimuscarinic effect on gut motility. Bioavailability is only 30 to 70 percent because of extensive "first pass" hepatic metabolism. They are highly protein bound to a acid glycoproteins. Their apparent volume of distribution is extremely large and ranges from 10 to 50 L/kg. Tissue TCA levels are commonly 10 to 100 times greater than plasma levels. Only 1 to 2 percent of the total body burden of TCAs is found in the blood. These pharmacokinetic properties explain why attempts at removing TCAs by hemodialysis, hemoperfusion, peritoneal dialysis, or forced diuresis are generally unproductive.

TCAs are eliminated almost entirely by hepatic oxidation, which consists of W-demethylation of the amine side-chain groups and hydroxylation of ring structures. The removal of a methyl group from the tertiary amine side chain usually produces an active metabolite designated by the desmethyl prefix (see TaMeJ...5.2:i.). These active metabolites often will have different pharmacologic activities when compared with the parent compounds. Amoxapine and maprotiline both have active metabolites. Although secondary amines such as desipramine, nortriptyline, and protriptyline are effective antidepressants, their metabolites are generally considered inactive. Clinical toxicity from tertiary TCAs usually lasts longer than that from secondary TCAs alone because of the production of active metabolites. Some TCAs undergo enterohepatic circulation prior to their eventual oxidation, conjugation, and renal elimination, but this does not significantly contribute to their toxicity.

The average elimination half-life of TCAs is approximately 24 h (range 6-36 h) at therapeutic doses, but this can increase to 72 h after overdose. Inhibition of TCA metabolism by other drugs that use the same hepatic enzymes can prolong the half-life of TCAs. This carries the risk of elevating TCA plasma levels and producing clinical TCA toxicity at therapeutic doses. Approximately 7 percent of the U.S. population are genetically slow metabolizers of TCAs. This predisposes them to develop higher plasma levels at any given daily TCA dose.

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