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Drug Metabolism and Disposition Fast Forward
First published on January 7, 2005; DOI: 10.1124/dmd.104.002782

0090-9556/05/3304-596-602$20.00
DMD 33:596-602, 2005

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BUCOLOME, A POTENT BINDING INHIBITOR FOR FUROSEMIDE, ALTERS THE PHARMACOKINETICS AND DIURETIC EFFECT OF FUROSEMIDE: POTENTIAL FOR USE OF BUCOLOME TO RESTORE DIURETIC RESPONSE IN NEPHROTIC SYNDROME

Norito Takamura1, Toru Maruyama, Etsuo Chosa, Keiichi Kawai, Yasuhiro Tsutsumi, Yukie Uryu, Keishi Yamasaki, Tsuneo Deguchi, and Masaki Otagiri

Department of Pharmacy, Miyazaki Medical College Hospital, Miyazaki, Japan (N.T., K.Y.); Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan (T.M., Y.T., Y.U., T.D., M.O.); Department of Orthopedic Surgery, Miyazaki Medical College, Miyazaki, Japan (E.C.); and School of Health Sciences, Faculty of Medical Kanazawa University, Kanazawa, Japan (K.K.)

To determine whether bucolome (5-n-butyl-1-cyclohexyl-2,4,6-trioxoperhydropyrimidine), a nonsteroidal anti-inflammatory agent, can reverse diuretic resistance of furosemide in patients with nephrotic syndrome, we examined the inhibitory effect of bucolome on the protein binding of furosemide in serum and urine. Bucolome significantly inhibited the protein binding of furosemide not only in serum but also in urine of preparation albumin (UPA), which mimics urinary albumin concentration in patients with nephrotic syndrome by ultrafiltration method. The binding percentage of furosemide to albumin was approximately 70% in UPA. With coadministration of bucolome to healthy volunteers, renal clearance of furosemide was increased, reflecting the increase of the free fraction of furosemide in serum. Furthermore, coadministration of bucolome caused a significant increase of urine volume and sodium concentration in urine. Even at higher urine levels of furosemide, the inhibitory effect of bucolome on the protein binding of furosemide in UPA remains constant, and changes in pH at weakly acidic pH levels (pH 5.5-6.5) did not alter the inhibitory effect of bucolome. Interestingly, coadministration of bucolome with furosemide in doxorubicin (Adriamycin)-induced nephrotic syndrome model rats alleviated the diuretic resistance. These results suggest that bucolome has a potent inhibitory effect on the protein binding of furosemide in the urine and can partially restore the diuretic response of furosemide in patients with nephrotic syndrome by increasing the free fraction of furosemide at the site of action.

Address correspondence to: Professor Masaki Otagiri, Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan. E-mail: otagirim{at}gpo.kumamoto-u.ac.jp




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