Disposition of propafenone in a poor metabolizer of CYP2D6 with Gilbert's syndrome.
Gilbert's syndrome, a genetic deficiency in bilirubin UDP-glucuronosyltransferase (UGT1A1), may dispose to increased toxicity of propafenone in poor metabolizers (PMs) of cytochrome P4502D6 because glucuronidation of propafenone 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. Using stable isotope techniques, the pharmacokinetics of single doses of 140 mg propafenone i.v. (unlabelled) and 300 mg propafenone p.o. (labelled) were compared between the index patient and the five healthy controls. Propafenone did not accumulate in the plasma of the index patient either before or during induction: AUC(0-infinity) of propafenone in the index patient was within the 95% confidence interval of controls; AUC(0-infinity) of propafenone glucuronide and amount of urinary excretion of propafenone glucuronide in the patient were within or even greater than the 95% confidence intervals of controls. Therefore, individuals with Gilbert's syndrome who also have a PM phenotype appear to be at no higher risk for toxicity of propafenone than otherwise healthy PMs. An indirect conclusion from these in vivo data might be that propafenone is not a substrate of the UGT1A1 isoform.[1]References
- Disposition of propafenone in a poor metabolizer of CYP2D6 with Gilbert's syndrome. Dilger, K., Meisel, P., Hofmann, U., Eichelbaum, M. Therapeutic drug monitoring. (2000) [Pubmed]
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