Partition of N-monodemethylated phenothiazine drugs to phosphatidylcholine bilayer vesicles studied by second-derivative spectrophotometry.
The partition coefficients (Kps) of three N-monodemethylated metabolites of phenothiazines (chlorpromazine (CPZ), triflupromazine, and promazine) between phosphatidylcholine (PC) vesicles (SUV) and water were determined to evaluate their affinity to biomembranes by second-derivative spectrophotometry without any separation procedures. The second derivative spectra showed distinct derivative isosbestic points confirming the entire elimination of the residual background signal effects of the SUV, which were observed in the absorption spectra. From the relationship between PC SUV concentration and the derivative intensity change (DeltaD) of each metabolite induced by its interaction with the PC bilayer, the Kp values were calculated and could be obtained with the R.S.D. of below 10% (n = 5) proving an accuracy of the derivative method. The obtained Kp values were similar to those of the parent drugs (the relative differences were within 15%), although the partition coefficient of N-monodemethylated CPZ measured in an octanol/buffer system was reported to be about 1/18 of CPZ. The results obtained from the PC liposome/buffer system do not contradict with psychoactivity and brain accumulation of N-monodemethylated metabolites of phenothiazines, in contrast to the results of the octanol/buffer system.
Takegami
Shigehiko
S
Kyoto Pharmaceutical University, 5 Nakauchicho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
Kitamura
Keisuke
K
Takahashi
Keiko
K
Kitade
Tatsuya
T
D014150:Antipsychotic Agents / Q000737:chemistry / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry*; D008745:Methylation; D010640:Phenothiazines / Q000737:chemistry* / Q000378:metabolism; D010713:Phosphatidylcholines / Q000737:chemistry*; D013053:Spectrophotometry
D014150:Antipsychotic Agents; D008051:Lipid Bilayers; D010640:Phenothiazines; D010713:Phosphatidylcholines; C031637:phenothiazine