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Decoctions of Hibiscus sabdariffa L. (Family Malvaceae) are very popular for the preparation of homemade refreshing drinks and are also used medicinally for a variety of ailments. Particularly remarkable are the various scientific reports supporting diuretic and antihypertensive potentials. It is therefore not unusual for patients who are on orthodox antihypertensive medications to use medicinal H. sabdariffa drinks concomitantly without regard to the possibility of herb–drug interactions. This possibility necessitated this study in which the pharmacokinetic and pharmacodynamic interactions of H. sabdariffa extract (HSE) and hydrochlorothiazide (HCT), a commonly prescribed diuretic drug, were examined. The effects of concomitant administration of HSE on urine volume, urine pH, and urinary concentrations of sodium, bicarbonate, and chloride ions, as well as on the pharmacokinetic parameters of HCT, were determined in experimental rats and rabbits. Co-administration of HSE with HCT caused a significant increase in the volume of urine excreted and resulted in a decrease in the pH of urine and the concentrations of sodium, bicarbonate, and chloride ions. Co-administration of HSE (20–40 mg/kg) with HCT (10 mg/kg) increased and prolonged the plasma concentration, the mean area under the concentration–time curve, and the volume of distribution of HCT achieved over the 24-hour sampling period. The plasma clearance and the elimination rate constant of HCT decreased with increasing dose of HSE co-administered with the HCT. The results of this study reveal a possible herb–drug interaction involving HCT and HSE, used as an ingredient in medicinal or refreshing drinks in many countries.