Disposition of propafenone in a poor metabolizer of CYP2D6 with Gilbert's syndrome

Gilbert's syndrome, a genetic deficiency in bilirubin UDP-glucuronosyl-tran sferase (UGT1A1), may dispose to increased toxicity of propafenone in poor metabolizers (PMs) of cytochrome P4502D6 because glucuronidation of propafe none is the major metabolic pathway for drug elimination in PMs. A patient with Gilbert's syndrome who is also PM participated in an interaction study with propafenone and rifampicin along with five otherwise healthy PMs. Usi ng stable isotope techniques, the pharmacokinetics of single doses of 140 m g propafenone i.v. (unlabelled) and 300 mg propafenone p.o. (labelled) were compared between the index patient and the five healthy controls. Propafen one did not accumulate in the plasma of the index patient either before or during induction: AUC((o-infinity)) of propafenone in the index patient was within the 95% confidence interval of controls; AUC((o-infinity)) of propa fenone glucuronide and amount of urinary excretion of propafenone glucuroni de in the patient were within or even greater than the 95% confidence inter vals of controls. Therefore, individuals with Gilbert's syndrome who also h ave a PM phenotype appear to be at no higher risk for toxicity of propafeno ne than otherwise healthy PMs. An indirect conclusion from these in vivo da ta might be that propafenone is not a substrate of the UGT1A1 isoform.