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 μg 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.

Introduction

Propafenone (PPF), a commonly used antiarrhythmic agent, is given clinically as a racemic mixture of S-PPF and R-PPF [1]. The two enantiomers are metabolized at different rates in Caucasians, with the R-PPF being eliminated faster than the S-PPF [2]. Propafenone is biotransformed mainly through cytochrome P450 2D6 (CYP2D6) to the active metabolite 5-hydroxypropafenone (5-OH PPF) and less importantly through CYP3A4 to N-desalkylpropafenone (N-desalkyl PPF). Previous work has shown that the metabolism of PPF is polymorphic and genetically determined, resulting in higher plasma drug concentrations in the 7% of Caucasians who are poor metabolizers (PMs) with respect to CYP2D6 [3]. Our recent research on dextromethorphan metabolic phenotyping in a Chinese population has shown that Chinese extensive metabolizers (EMs) consisted of about 99% (119/120) of the Chinese population and that only one subject could be classified as a PM with respect to CYP2D6 [4]. The purpose of this study was to examine the dispositon of propafenone enantiomers in 16 EMs and one PM to determine if stereoselective pharmacokinetics of propafenone occurs and whether the kinetics of propafenone enantiomers depends on CYP2D6 activity in Chinese subjects.

Methods

Subjects

Seventeen (eleven men and six women) healthy native Chinese subjects (age range, 23 to 45 years; weight range, 50 to 75 kg) were recruited from our previous study population of 120 volunteers undergoing dextromethorphan metabolic phenotyping of CYP2D6 [4]. Sixteen subjects (10 men, 6 women) were classified as EMs (lg MR<−0.52) and one subject (male) as a PM (lg MR≥−0.52). All subjects were healthy as assessed by the medical history, physical examination, electrocardiograms, and routine laboratory testing. All were non-smokers and drug free for at least 2 weeks before and during the study. The study was approved by the Hospital Ethics Committee. Informed consent was obtained from all subjects.

Protocol

After an overnight fast, subjects received 400 mg rac-propafenone hydrochloride tablets (XingYi Pharmaceutical Company, Shanghai, China, Lot No. 96100037) orally. An intravenous catheter was inserted into the vein in either arm of each subject, and blood samples were drawn at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 15 h after drug administration. Plasma was separated and stored at −20° C until assay.

Drug measurement and data analysis

Propafenone enantiomers were determined by a reverse-phase high performance liquid chromatography (h.p.l.c.) method established in our laboratory [5]. The limits of detection of S-PPF and R-PPF were 10 ng ml⁻¹ and 13 ng ml⁻¹, respectively. The average intraday and interday CV were all below 6%, and average recovery was 102.2%.

The pharmacokinetic parameters (k, t_1/2, C_max, t_max) of propafenone enantiomers were obtained from a PKBP-N1 computer program with one-compartment simulation [6]. Area under the plasma concentration-time curve (AUC) was determined by the trapezoidal rule and extrapolated to infinity by calculation of C_t/k, where C_tis the last plasma concentration determined at 15 h. Apparent oral clearance (CL) was calculated as dose/AUC. Differences in the pharmacokinetics between S-PPF and R-PPF were tested by the t-test for paired samples. A P value of less than 0.05 was regarded as statistically significant. 95% Confidence intervals (95% CI) for differences in means were also calculated. The Spearman rank test was used to determine the degree of association between pharmacokinetic parameters of propafenone enantiomers and dextromethorphan metabolic ratio (MR). Data are shown as mean±s.d.

Results

Figure 1 shows the plasma concentration-time profile of propafenone enantiomers in 16 Chinese EMs and one PM with respect to CYP2D6 after a single oral dose (400 mg) of rac-propafenone hydrochloride. There were significant differences in the stereoselective disposition among subjects between S-PPF and R-PPF. For the EM subjects, S-PPF was less rapidly metabolized and had higher peak plasma concentrations (413±143 ng ml⁻¹) than R-PPF (291±109 ng ml⁻¹) (difference: 122±61 ng ml⁻¹, 95% CI: 89∼154 ng ml⁻¹, P<0.001). The AUC was markedly higher for S-PPF (2214±776 μg l⁻¹ h) than for R-PPF (1639±630 μg l⁻¹ h) (difference: 575±273 μg l⁻¹ h, 95% CI: 430∼720 μg l⁻¹ h, P<0.001), whereas, the clearance of S-PPF (96.0±39.0 l h⁻¹) was significantly lower than that of R-PPF (138±78 l h⁻¹) (difference: 41.9±47.6 l h⁻¹, 95% CI: 16.5∼67.3 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 be less rapidly metabolized 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 the dextromethorphan metabolic ratio (log MR) and the 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 (Figure 2). Intake of propafenone was associated with dizziness in five subjects (four EMs and one PM). The PM subject also experienced gastrointestinal symptoms (nausea and gastric irritation) and dizziness which persisted for 10 h.

Figure 1.

Plasma concentration-time profile of propafenone enantiomers among 16 Chinese EMs (a) and one PM (b) with respect to CYP2D6. ○ S-PPF, Δ R-PPF.

Figure 2.

Correlation between the dextromethorphan metabolic ratio and the C_max, oral CL and AUC of S-propafenone (a) and R-propafenone (b) in 16 Chinese EMs (open circles) and one PM (solid circles).

Discussion

Propafenone, a drug with a narrow therapeutic range, undergoes stereoselective disposition and is subject to a genetic polymorphism in its metabolism, which is mediated by CYP2D6 [7]. For Chinese, especially those living in mainland China, studies on the enantiomeric disposition of propafenone and its relationship to CYP2D6 activity are limited. Kuang et al.studied propafenone pharmacokinetics in eight Chinese EM and one PM [8]. Although substantial variability in the pharmacokinetic parameters (t_1/2, AUC, CL) were found, they were not correlated with CYP2D6 activity. Likewise, Zhong et al.investigated the stereoselective pharmacokinetics of propafenone enantiomers in 10 healthy Chinese subjects [9], but did not relate them to CYP2D6 activity.

The present investigation is the first to describe the role of genetically determined CYP2D6 activity in the disposition of propafenone enantiomers in Chinese subjects. We found R-propafenone was preferentially eliminated in both the EMs and the one PM subjects. The latter achieved a 2∼3 fold higher plasma drug concentrations of both enantiomers compared to EMs as a result of lower clearance. Our results are similar to those in Caucasians [7]. Furthermore, there was a significant correlation between the pharmacokinetics of propafenone enantiomers and the dextromethorphan MR. Thus, our study suggests that CYP2D6 activity contributes to the variability in pharmacokinetics of propafenone in Chinese subjects.