The influence of CYP2D6 activity on the kinetics of propafenone enantiomers in Chinese subjects

Abstract

Aims To determine role of CYP2D6 activity in the pharmacokinetics of propafenone (PPF) enantiomers in native Chinese subjects. Methods Sixteen extensive metabolizers (EMs) and one poor metabolizer (PM), whose phenotype had been previously assessed with dextromethorphan metabolic phenotyping, were enrolled. Blood samples (0~15 h) were taken after oral administration of a single dose (400 mg ) of racemic-propafenone hydrochloride. A reverse-phase h.p.l.c. method with pre-column derivatization was employed to quantitate enantiomeric concentrations of propafenone in plasma. Results For the EM subjects, S-PPF was less rapidly metabolized and had higher peak plasma concentrations than R-PPF (413±143 vs 291±109 ng ml −1 , P<0.001).The AUC was markedly higher for S-PPF than for R-PPF (2214±776 vs 1639±630 mg h l −1 , P<0.001), whereas the clearance of S-PPF was significantly lower than that of R-PPF (96.0±39.0 vs 138±78 l h −1 , P<0.01). There were no differences in t 1/2 , and C max between the two isomers ( P >0.05). In the one PM subject, not only did S-PPF appear to undergo less rapid metabolism than R-PPF, but the subject also showed 2~3 fold differences in C max , CL and AUC compared with EMs. The correlation coefficients (r s ) between dextromethorphan metabolic ratio (lg MR) and pharmacokinetic parameters (C max , CL and AUC) were 0.63, −0.87, 0.87 for S-PPF and 0.57, −0.73, 0.86 for R-PPF, respectively. Conclusions Our results suggest that CYP2D6 activity contributes to the pharmacokinetic variability of propafenone enantiomers in Chinese subjects.Keywords: propafenone, enantiomer, pharmacokinetics, CYP2D6, phenotype, Chinese metabolic phenotyping in a Chinese population has Introduction shown that Chinese extensive metabolizers (EMs) consisted of about 99% (119/120) of the Chinese population Propafenone (PPF), a commonly used antiarrhythmic agent, is given clinically as a racemic mixture of S-PPF and that only one subject could be classified as a PM with respect to CYP2D6 [4]. The purpose of this study and R-PPF [1]. The two enantiomers are metabolized at different rates in Caucasians, with the R-PPF being was to examine the dispositon of propafenone enantiomers in 16 EMs and one PM to determine if stereoselective eliminated faster than the S-PPF [2]. Propafenone is biotransformed mainly through cytochrome P450 2D6 pharmacokinetics of propafenone occurs and whether the kinetics of propafenone enantiomers depends on CYP2D6 (CYP2D6) to the active metabolite 5-hydroxypropafenone (5-OH PPF) and less importantly through activity in Chinese subjects. CYP3A4 to N-desalkylpropafenone ( N-desalkyl PPF). Previous work has shown that the metabolism of PPF is Methods polymorphic and genetically determined, resulting in higher plasma drug concentrations in the 7% of Caucasians Subjects who are poor metabolizers (PMs) with respect to Seventeen (eleven men and six women) healthy native CYP2D6 [3]. Our recent research on dextromethorphan Chinese subjects (age range, 23 to 45 years; weight range, 50 to 75 kg) were recruited fr...

Influence of CYP2D6 genetic variation on adverse events with propafenone in the pediatric and young adult population

“…Studies focused on specific CYP2D6 alleles and propafenone drug concentrations have demonstrated that CYP2D6 poor metabolizers had higher drug concentrations. 9,[27][28][29][30] An adult study utilizing debrisoquine as phenotype probe and urinary metabolic ratios, which serves as a surrogate measure of CYP2D6 activity, reported an increased risk of neurologic AEs with propafenone in poor metabolizers compared to ultrarapid metabolizers. 16 Similarly, in our study a significant association between activity score and systemic AEs was observed.…”

“…AEs were seen in 29 (38%) individuals in this cohort. The most common AEs (Figure 1) were prolonged QRS (median increase of 18 [16][17][18][19][20][21][22][23][24][25][26][27] ms; n = 10) and QTc intervals (median increase 20 ms; n = 6). Those without QRS prolongation had median increase in QRS of 10 (−1, 16) ms. Those without QTc prolongation had average increase in QTc of 5 (−8, 40) ms. Baseline median intervals for QRS and QTc amongst all patients were 78 (68-96) ms and 442 (417-466) ms, respectively.…”

Fluoxetine impairs the CYP2D6-mediated metabolism of propafenone enantiomers in healthy Chinese volunteers

“…The metabolism of propafenone has been found to be genetically determined and polymorphic, with poor metabolizer status in about 7% of white subjects associated with higher plasma concentrations of propafenone and therefore potential higher incidence of central nervous system side effects and cardiac β‐blockade 4 . Our recent study in 17 Chinese subjects indicated that disposition of propafenone enantiomers is genetically determined by CYP2D6 activity, with a twofold to threefold higher plasma concentration of two enantiomers in poor metabolizers compared with extensive metabolizers 5 …”

“…4 Our recent study in 17 Chinese subjects indicated that disposition of propafenone enantiomers is genetically determined by CYP2D6 activity, with a twofold to threefold higher plasma concentration of two enantiomers in poor metabolizers compared with extensive metabolizers. 5 We therefore anticipated that the metabolism and side effects of propafenone may be affected by coadministration of CYP2D6 inhibitors, such as fluoxetine, in Chinese patients with arrhythmias and depression. The purpose of this study was to determine the effect of a therapeutic dose (20 mg/day) of fluoxetine on the pharmacokinetics of propafenone enantiomers and CYP2D6 activity with use of dextromethorphan O-demethylation as a probe in nine healthy Chinese volunteers.…”