Protein Binding of Chlorpromazine in Vivo and in Vitro : Effect of Chlorpromazine Metabolite on Chlorpromazine Protein Binding in Rat

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The serum protein binding curve of chlorpromazine (CPZ) on the Scatchard plot in vitro was a two-phase downward curve. However, after i.v. administration of CPZ the curve was altered to an upward curve. To clarify the reasons for these in vivo changes, the influence of chlorpromazine S-oxide (CPZSO), chlorpromazine N-oxide (CPZNO), desmethylchlorpromazine (nor1-CPZ), chlorpromazine sulfone (sul-CPZ) and 7-hydroxychlorpromazine (7-OH-CPZ) on CPZ protein binding were studied in vitro. The results indicated that the characteristics of the CPZ protein binding are altered by the combination of CPZSO or CPZNO or by either of them. Since it was very difficult to explain the relationship between serum total and free concentrations of CPZ in vivo using mass-balance equations like Hill's equation or a competitive inhibition equation on the multiple binding sites for drug, the correlation between the ratio of total concentration of CPZ metabolites and CPZ (CPZSO/CPZ or CPZNO/CPZ) and the free fraction of CPZ was examined using the in vitro and in vivo data. The correlation between the ratio of CPZSO/CPZ and the free fraction of CPZ was good in both the in vivo and the in vitro studies. There was no statistically significant difference between the population regression coefficient of the two studies. The values of the slope and the intercept became almost the same as those obtained using the in vivo studies when combined with CPZNO. The results indicated that 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.
社団法人日本薬学会の論文
1995-04-15

Protein Binding of Chlorpromazine in Vivo and in Vitro : Effect of Chlorpromazine Metabolite on Chlorpromazine Protein Binding in Rat

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