Effect of platinum coordination complex (PtCx) on citrate uptake by rat renal brush border membrane vesicles (BBMV): direct effect of carboplatin.

Inhalation of platinum, as soluble salts, is known to cause respiratory distress and severe dermatitis in workers. Platinum coordination complexes are widely used in the treatment of a variety of solid tumors. However, the clinical use of cisplatin (CDDP) (the most useful agent) is limited by the development of nephrotoxicity. High dose accidental exposure to soluble platinum in platinum refineries and pharmaceutical factories could induce occupational nephrotoxicity. Carboplatin (CBDCA), a second-generation platinum coordination complex, is highly effective against a variety of malignancies at doses five- to ten-times higher than CDDP. At therapeutic doses, CBDCA is less nephrotoxic than CDDP. Additionally, urinary citrate is freely filtered at the glomerulus, and its reabsorption in the proximal tubule is the major determinant of the rate of renal excretion. In our previous study, the preincubation of rat renal brush border membrane vesicles (BBMV) with 5 mM cisplatin for 4 and 8 hours significantly inhibited the citrate uptake compared with that of the control BBMV. In this study, we exposed BBMV to 100 mM carboplatin (twenty-times higher concentration than cisplatin) and examined the citrate uptake characteristics to clarify the toxic mechanism of platinum coordination complexes. The preincubation of BBMV with 100 mM carboplatin for 8 hours also significantly inhibited the citrate uptake compared with that of the control BBMV, but the alterations were not as severe as those with 5 mM cisplatin.