Influence of renal function on the steady-state pharmacokinetics of the antiarrhythmic propafenone and its Phase I and Phase II metabolites

Abstract

The aim of this study was to investigate the disposition of propafenone and its Phase I and II metabolites in relation to kidney function under steady-state conditions. The mechanism of the renal handling of propafenone glucuronides (filtration, secretion) was also examined. Racemic (R/S) propafenone was administered to 7 young volunteers, to 5 older patients with a normal glomerular filtration rate and to 4 patients with chronic renal failure. No difference was found in the plasma concentrations of propafenone and 5-hydroxypropafenone between the three groups. The propafenone glucuronide (PPFG) concentration was elevated in the older compared to the younger subjects (S-PPFG: 544 vs. 222 nmol · ml⁻¹ · mol⁻¹; R-PPFG: 576 vs. 304 nmol · ml⁻¹ · mol⁻¹). Although Glomerular filtration rate did not differ, the renal clearance of propafenone glucuronides was reduced in the former group, which could be attributed to their impaired renal secretion. A dramatic increase in propafenone glucuronide concentration was observed in the patients with renal failure (S-PPFG: 2783 nmol · ml⁻¹ · mol⁻¹; R-PPFG: 7340 nmol · ml⁻¹ · mol⁻¹). In summary, the disposition of propafenone and of its active metabolite 5-hydroxypropafenone was not affected by kidney dysfunction, indicating that no dose adjustment is necessary in patients with renal failure. The accumulation of drug glucuronides in older patients with apparently normal kidney function should be taken into account as a possible factor modifying drug therapy.