Tca pharmacokinetics

TCAs are well absorbed upon oral administration. Because of their lipophilic nature, they are widely distributed and readily penetrate into the CNS. This lipid solubility also causes these drugs to have variable halflives (for example, 4 to 17 hours for imipramine). As a result of their variable first-pass  metabolism in the liver, TCAs have low and inconsistent bioavailability. Therefore, the patient’s response and plasma levels can be used to adjust dosage. The initial treatment period is typically 4 to 8 weeks. The dosage can be gradually reduced to improve tolerability, unless relapse occurs. These drugs are metabolized by the hepatic microsomal system (and, thus, may be sensitive to agents that induce or inhibit the CYP450 isoenzymes) and conjugated with glucuronic acid. Ultimately, the TCAs are excreted as inactive metabolites via the kidney. They have high volumes of distribution and are not readily dialyzable. Extensive hepatic metabolism is required before their elimination; plasma half-lives of 8–36 h usually permit once-daily dosing.