天津药物研究院学术会议.ppt

Study Design (Continued)Inhibition and Induction Effects of RIF on Glyburide Rifampin 600mg P.O. for 6 days Rifampin 600mg I.V. Glyburide 1.25mg P.O. (PK study) Glyburide 1.25mg P.O. (PK study) ALL Healthy Volunteers Visit 3 Day 15 Visit 4 Day 17 Cmax 81% T1/2 31% AUC0-inf 125% CL/F 53% Vss/F 60% Inhibition of Glyburide Uptake by IV RIF * * * * * * P0.05 Cmax 48% AUC0-inf 63% CL/F CYP450 Induction Effect on Glyburide When No RIF Present in the Plasma * * * 197% Vss/F 32% ns Cmax 9% AUC0-inf 22% CL/F 37% Uptake Inhibition and CYP450 Induction Effects on Glyburide When RIF Present in the Plasma * * Vss/F 43% * PD Effects: Change of Blood Glucose Level-Time Curve SINGLE IV DOSE OF RIFAMPIN SIGNIFICANTLY INCREASED THE THERAPEUTIC EFFECT OF GLYBURIDE Breakfast Lunch Dinner 0 4 8 12 -30 -20 -10 0 10 20 30 Glyburide Control RIF IV+Glyburide RIF IV+Glyburide After RIF Induction Glyburide After RIF Induction Time (h) Change in Blood Glucose Level (mg/dl) High Solubility Low Solubility High Permeability Low Permeability Class 2 Fextent Tpeak Class 1 Fextent Tpeak Class 3 Fextent Tpeak Class 4 Fextent Tpeak Food Effects (High Fat Meals)Fleisher et al., Clin Pharmacokinet.36(3):233-254, 1999 We hypothesize that high fat meals inhibit transporters Preliminary results suggest that the inhibitors are the monoglycerides found in high fat meals (J.M. Custodio, C-Y. Wu and L.Z.Benet, Adv. Drug Deliv. Rev. 60:717-733, 2008) Conclusions Understanding transporter-enzyme interactions in terms of the permeability and solubility of drug compounds offers the potential for predicting: Major routes of elimination Transporter effects of drug absorption Food (High Fat Meal) effects Transporter effects on post absorption systemic levels and after i.v. dosing Enzyme transporter interplay Drug-drug interaction potential and its relationship to enzyme-transporter interplay Conclusions g. Previously unexplained effects of