Inhibitory Effect of Uraemia on the Hepatic Clearance and Metabolism of Nicardipine

1. The principal aim of this study was to investigate the effect of renal impairment on the pharmacokinetics of nicardipine following intravenous and oral dosing. 2. The plasma clearance of nicardipine was significantly lower at 6.5 ml min-1 kg-1 in patients with impaired renal function, compared with a mean value of 10.4 in patients with normal renal function and with 12.5 ml min-1 kg-1 in patients on regular haemodialysis treatment. 3. In comparison to the patients with normal renal function, there were significant increases in AUC and Cmax in the patients with renal impairment. These increases were particularly marked during chronic dosing - AUC was increased by 163%, Cmax by 127% and apparent oral bioavailability by 90%. There were no such increases in the dialysis group whose values were similar to those for normal renal function. 4. There were no significant differences in volume of distribution or protein binding, nor in the measured indices of hepatic function to account for the reduction in drug clearance in the patients with renal impairment. 5. The results of this study indicate that renal impairment may have a significant and potentially important impact on the disposition of a drug which, under normal circumstances, is highly extracted by the liver. Accumulation of a metabolic 'inhibitor' substance is a possible explanation.