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The applicability and effectiveness of the proposed method for the determination of furosemide and spironolactone in patient urine samples were tested. In comparison with reference methods, the attained results demonstrated that SBME combined with HPLC-DAD was proved to be simple, inexpensive, and promising analytical technology for the simultaneous determination of furosemide and spironolactone in urine and plasma samples. In comparison with reference methods, the attained results demonstrated that SBME combined with HPLC-DAD was proved