Several piperazine phenothiazines are esterified at a free hydroxyl with long-chain fatty acids to produce highly lipophilic and long-acting prodrugs. They tend to have large volumes of distribution, probably because they are sequestered in lipid compartments of the body and have very high affinity for selected NT receptors in the CNS. They generally have a much longer clinical duration of action than would be estimated from their plasma half-lives. This is paralleled by prolonged occupancy of DA D2 receptors in brain. The decanoates of fluphenazine and haloperidol are used commonly in the United States; several others (including esters of pipotiazine and perphenazine) are available elsewhere.

Because of the high lipophilicity of most antipsychotic drugs, they are highly membrane and protein bound (92%-99%) mostly to albumin. They accumulate in the brain, lung, and other tissues with a rich blood supply and also enter the fetal circulation and breast milk.

Most phenothiazines undergo significant first-pass metabolism. Chlorpromazine and other phenothiazines are metabolized extensively by CYP2D6. Thus, oral doses of chlorpromazine and thioridazine have systemic availability of 25% to 35%, whereas parenteral (intramuscular) administration increases the bioavailability of active drug fourfold to tenfold. In contrast, haloperidol, which is less likely to be metabolized, has an average systemic availability of about 65%. Metabolism of the phenothiazines is complex in detail.

A major route is 7-hydroxylation of the tricyclic system. Because electron-withdrawing 2-Cl substituent blocks the hydroxylation on chlorophenyl ring, the hydroxylation occurs at 7-position rather than 2-position. Thus, the major initial metabolite is frequently the 7-hydroxy compound (active metabolite). This compound is further metabolized by conjugation with glucuronic acid, and the conjugate is excreted. Metabolites of chlorpromazine may be excreted in the urine weeks after the last dose of chronically administered drug. Full relapse may not occur until 6 weeks or more after discontinuation of many antipsychotics. Detailed reviews of the metabolites of phenothiazines (as well as SARs and pharmacokinetic factors) are available.31

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