Influence of release rate, dose and co-administration on pharmacokinetics, pharmacodynamics and PK-PD relationship of tanshinone IIA and tanshinol

The present study aims to investigate the influence of release rate, dose and co-administration on pharmacokinetics (PK) and pharmacodynamics (PD) of tanshinone IIA (TA) and tanshinol (TS), and reveal the changes in their PK-PD relationships. Sustained and immediate release pellets of TS and TA were prepared respectively, and oral administrated to angina model rabbits according to the experimental design. The administration dose of TS was 50, 35 or 20 mg/kg and that of TA was 30 mg/kg. Then, plasma concentrations of TS and TA were measured to evaluate the pharmacokinetics. Pharmacodynamic biomarkers including cardiac troponin (cTn-I), creatine kinase (CK-MB), superoxide dismutase (SOD) and nitric oxide (NO) were measured to evaluated the effects of cardioprotection, amelioration of oxidative stress and vasorelaxation of TS and TA. Parameters such as maximum plasma concentration (Cmax), maximum effect (Emax), time to Cmax or Emax (TCmax or TEmax), areas under the plasma concentration or effect curves (AUC0-∞ or AUEC) and pharmacodynamic efficiency (EFF) were calculated based on non-compartmental analysis. Beside, PK-PD relationship/hysteresis was evaluated. The TEmax was less sensitive than TCmax to changes in release rate. The Emax, AUEC and EFF showed increasing trend as the decrease of release rate even that the AUC0-∞ showed no significant difference. In addition, slow drug release decreased the magnitude of hysteresis of TS and TA. The sensitivities of Emax and AUEC of four biomarkers to changes in dose were varied and relatively lower than those of Cmax and AUC0-∞. The EFF decreased and the magnitude of hysteresis increased for high dose. The Cmax and AUC0-∞ of TS and TA showed little difference after co-administration. The Emax and AUEC of four biomarkers increased for immediate release pellets (P < 0.05 or P < 0.01) and generally decreased for sustained release pellets (P < 0.05 or P < 0.01) after co-administration. In addition, the magnitudes of hysteresis of four biomarkers decreased for immediate release pellets and generally increased for sustained release pellets after co-administration. In summary, the dissociated and unstable PK-PD relationship should be considered during optimization of dosage forms and regimens to make sure the rationality, safety and efficacy. These findings could also provide some valuable information for the development and clinical therapy of other drugs.