A comparative study of chlorpromazine and its demethylated derivatives: Potency and tissue distribution

Partition of N‐Monodemethylated Phenothiazine Drugs to Phosphatidylcholine Bilayer Vesicles Studied by Second‐Derivative Spectrophotometry

“…Although the differences of K p values between the N ‐monodemethylated metabolites and their parent drugs are shown to be significant by a Student's t test ( p < 0.05), the differences are within 15%. This result is largely different from that obtained for the organic solvent/buffer systems,3,5 i.e., the APC of CPZ and Nor1–CPZ at pH 7.4 are 18.7 and 8.9 in benzene/buffer, 31.3 and 19.2 in chloroform/buffer, 2480 and 138 in octanol/buffer systems, respectively.…”

“…The phenothiazine antipsychotics are extensively metabolized in the body to produce a wide variety of metabolites, and some of them are psychoactive to contribute to clinical improvement 1. Chlorpromazine (CPZ) is the most frequently prescribed phenothiazine drug, and its N ‐monodemethylated metabolite, Nor1–CPZ, is an active metabolite 2,3. It has been also reported that Nor1–CPZ accumulates in the brain to a greater extent than another CPZ metabolites,3 and its relative amount in the plasma level of psychotic patients is about 17% of the parent drug, CPZ 4…”

“…However, the apparent partition coefficient (APC) of Nor1–CPZ in organic solvent/buffer system3,5 is reported to be very small compared to the parent CPZ. This implies that the affinity of Nor1–CPZ to biomembranes is very weak, i.e., the APC obtained for organic solvent/buffer system does not correlate to the facts of psychoactivity and brain accumulation of Nor1–CPZ 3. Thus, further investigation on the interaction of N ‐monodemethylated phenothiazine metabolites with biomembranes should be necessary.…”