Simultaneous modeling of pharmacokinetics and pharmacodynamics of propafenone in healthy subjects.
OBJECTIVE
To study the simultaneous modeling of pharmacokinetics and pharmacodynamics (PK-PD) of propafenone (Pro) in healthy subjects.


METHODS
Ten healthy Chinese volunteers, 5 extensive metabolizers (EM) and 5 intermediate metabolizers (IM) of CYP2D6, received a single dose (400 mg) of Pro hydrochloride. The blood samples and electrocardiogram (ECG) measurements were taken after administration over 15 h period. The concentrations of Pro in plasma were measured by a reverse-phase HPLC. PR interval was used as an average value of 10 PR interval measurements.


RESULTS
There was a delay between Pro level and percentage of PR interval prolongation. After PK-PD simulating, the relationship between effect concentration (Ce) and the effect met the sigmoid E(max) model. CYP2D6 (EM & IM) played an important role in both pharmacokinetics and pharmacodynamics which produced by Pro. The AUC (microg . h . L-1) of IM group was significantly higher than that of EM group (5126 +/- 1030 vs 2948 +/- 1230, P < 0.05). Whereas Ce50 (microg/L) was also greater in IM group than in EM group (747 +/- 281 vs 359 +/- 123, P < 0.05). On the other hand, gamma of EM group was about one fold larger than that of IM group (P < 0.05).


CONCLUSIONS
CYP2D6 phenotype of human may influence not only pharmacokinetic of Pro but also its pharmacological effects.
Cai
W M
WM
Institute of Clinical Pharmacology, Nanjing Medical University, Nanjing 210029, China. weimincai@hotmail.com
Zhang
Y D
YD
Chen
B
B
Cai
M H
MH
Luo
J P
JP
Ling
S S
SS
D000328:Adult; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D010641:Phenotype; D011110:Polymorphism, Genetic; D011405:Propafenone / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*
D011405:Propafenone; D019389:Cytochrome P-450 CYP2D6