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.

Assessment of individual CYP2D6 activity in extensive metabolizers with renal failure: Comparison of sparteine and dextromethorphan*

“…This is not surprising because dextrorphan is excreted in urine as a conjugate of glucuronic acid.24 A recent study with propafenone, which is in part excreted in urine as glucuronides, showed that the renal clearance of propafenone glucuronides decreases with age and even more so in patients with impaired renal function. 25 Thus it is likely that, in our study, the urinary excretion of dextrorphan was largely influenced by renal function because after the formation of dextrorphan by CYP2D6, its glucuronides could not be excreted in our patients with renal failure. We can-not rule out that if dextrorphan had been collected in urine over a longer period of time, better relationships between its fractional excretion and sparteine-based indexes of CYP2D6 activity could have been found.…”

Glucuronidation of piceatannol by human liver microsomes: major role of UGT1A1, UGT1A8 and UGT1A10

“…It is not known yet whether piceatannol conjugates also exhibit pharmacological activity. However, numerous studies have shown that glucuronides can accumulate during chronic therapy (31–33) . Cleavage of the glucuronides by human β‐glucuronidase, an enzyme expressed in many tissues and body fluids in humans, can release the parent compounds and thereby modify drug disposition (34) .…”

Pharmacokinetics of Isoliquiritigenin and Its Metabolites in Rats: Low Bioavailability Is Primarily Due to the Hepatic and Intestinal Metabolism

“…Particularly glucuronidation can be a major cause of change in pharmacological activities and pharmacokinetic phenomena. The increased hydrophilicity of glucuronidated metabolites changes the enterohepatic circulation, metabolism in the liver and intestine, as well as renal and biliary excretions of the parent compound and its metabolites, thus modifying the pharmacological activities [17,18]. Thus, the determination of the pharmacokinetic profiles of isoLQ as well as those of its metabolites may make it possible to figure out the substantial function of isoLQ in living organisms.…”