CALMODULIN INHIBITORS AND CALCIUM-CHANNEL BLOCKERS INFLUENCE DIDEOXYCYTIDINE RENAL EXCRETION

Renal handling of 2',3'-dideoxycytidine (ddC), a new anti-HIV dideoxyn ucleoside which undergoes renal and non-renal clearance, was determine d in CF-1 male mice. Since calmodulin inhibitors (CIs) and calcium cha nnel blockers (CCBs) have been shown to influence the flux of pyrimidi ne nucleosides across mammalian membranes and since the plasma concent ration (and hence the efficacy) of therapeutic nucleosides is usually affected by the rate of renal elimination, we decided to determine the impact of the CIs loperamide (LOP) and trifluoperazine (TFP) as well as the CCB verapamil (VER) on the renal excretion of ddC. The ratio of ddC clearance to inulin clearance suggests that ddC undergoes secreti on into renal tubules. Pre-exposure of mice to the calmodulin inhibito rs loperamide (LOP) and trifluoperazine (TFP) resulted in a decrease i n ddC renal secretion while pre-treatment with the calcium channel blo cker verapamil increased ddC secretion.