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BACKGROUND Numerous herbs are reported to have anti-hyperglycemic activity and are frequently used in combination with prescription drugs to lower the blood glucose levels in diabetic patients, without proper knowledge about possibility of herb-drug interaction. OBJECTIVES To investigate the effect of cumin and garden cress on pharmacokinetics (PK) and pharmacodynamics (PD) of gliclazide (GLZ) in nicotinamide-streptozotocin diabetic model. METHODS Diabetic animals of groups II-IV were treated with GLZ, cumin, 'cumin + GLZ', garden cress and 'garden cress + GLZ'. Herb's treatments were given for two weeks, and GLZ was administered in a single dose. Blood glucose levels (BGLs) were measured at pre-determined time points. Plasma samples of pharmacokinetic study were analyzed using UPLC-MS/MS. GLZ fragment at m/z 324.1>127 was monitored. RESULTS Cumin and garden cress have shown 15.3% and 15.9% reduction in mean BGL (1-24h) (p-value < 0.001), respectively. GLZ reduced mean BGL by 30.0%, which was significantly better than cumin and garden cress (p-value <0.05). Concurrently administered "garden cress + GLZ" demonstrated highest reduction in mean BGL (by 40.46%) and showed prolonged effect. There was no significant advantage of simultaneously administered 'cumin + GLZ'. Cumin did not affect PK of GLZ. Garden cress has significantly enhanced AUC0-t (by 69.8%, p-value 0.0013), but other PK parameters Cmax, Tmax, and Kel were close to control group. CONCLUSION PK/PD based herb-drug interaction was observed. Concurrently administered garden cress + GLZ showed improved antidiabetic effect and has enhanced GLZ bioavailability.