PROTEIN-BINDING OF CHLORPROMAZINE IN-VIVO AND IN-VITRO - EFFECT OF CHLORPROMAZINE METABOLITE ON CHLORPROMAZINE PROTEIN-BINDING IN RAT

The serum protein binding curve of chlorpromazine (CPZ) on the Scatcha rd plot in vitro was a two-phase downward curve. However, after i.v. a dministration of CPZ the curve was altered to an upward curve. To clar ify the reasons for these in vivo changes, the influence of chlorproma zine S-oxide (CPZSO), chlorpromazine N-oxide (CPZNO), desmethylchlorpr omazine (nor1-CPZ), chlorpromazine sulfone (sul-CPZ) and 7-hydroxychlo rpromazine (7-OH-CPZ) on CPZ protein binding were studied in vitro. Th e results indicated that the characteristics of the CPZ protein bindin g are altered by the combination of CPZSO or CPZNO or by either of the m. Since it was very difficult to explain the relationship between ser um total and free concentrations of CPZ in vivo using mass-balance equ ations like Hill's equation or a competitive inhibition equation on th e multiple binding sites for drug, the correlation between the ratio o f total concentration of CPZ metabolites and CPZ (CPZSO/CPZ or CPZNO/C PZ) and the free fraction of CPZ was examined using the in vitro and i n vivo data. The correlation between the ratio of CPZSO/CPZ and the fr ee fraction of CPZ was good in both the in vivo and the in vitro studi es. There was no statistically significant difference between the popu lation regression coefficient of the two studies. The values of the sl ope and the intercept became almost the same as those obtained using t he in vivo studies when combined with CPZNO. The results indicated tha t the influence of CPZNO on the correlation between the ratio of CPZSO /CPZ and the free fraction of CPZ is very small, and this correlation might. be able to be used for the analysis of pharmacokinetic studies of CPZ in vivo.