Effects of CYP2D6*10, CYP3A5*3, CYP1A2*1F, and ABCB1 C3435T polymorphisms on the pharmacokinetics of flecainide in healthy Chinese subjects.
BACKGROUND
Although flecainide is thought to be meta-bolized predominantly by cytochrome P450 (CYP) 2D6, it shows pharmacokinetic interactions with drugs, such as verapamil and digoxin, which may suggest other CYP pathways or ATP-binding cassette (ABC) transporters might be involved. This study evaluated effects of common polymorphisms in Chinese in CYP2D6, CYP3A5, CYP1A2, and ABCB1 on flecainide pharmacokinetics.


METHODS
Single oral 100-mg doses of flecainide were given to 15 healthy male Chinese subjects who were genotyped for the CYP2D6*2, *5, *10, CYP3A5*3, CYP1A2*1F and ABCB1 C1236T, G2677T/A, and C3435T polymorphisms.


RESULTS
There was no significant difference in the pharmacokinetics of flecainide among CYP2D6 (mainly involving *10) genotypes. The CYP3A5*3/*3 subjects (n=8) had a 26% higher systemic exposure (AUC0-∞) and 17% lower apparent oral clearance of flecainide than the combined group of CYP3A5*1/*1 (n=6) and CYP3A5*1/*3 (n=1) subjects (p<0.05). Subjects homozygous for CYP1A2*1F tended to have lower systemic exposure and increased clearance of flecainide compared to those with CYP1A2*1A/1F in subjects with at least one CYP2D6 variant allele.


CONCLUSIONS
The disposition of flecainide appeared to be influenced by the CYP3A5*3 and possibly the CYP1A2*1F polymorphisms, particularly in subjects with CYP2D6 variant alleles.
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, School of Pharmacy, Prince of Wales Hospital, Shatin, Hong Kong SAR.
Miao
M
Hu
Ya-Ling
YL
Yang
Benny S P
BS
Fok
Sze-Wa
SW
Chan
Tanya T W
TT
Chu
Emily W M
EW
Poon
Ophelia Q P
OQ
Yin
Vincent H L
VH
Lee
Brian
B
Tomlinson
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005424:Flecainide / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000889:Anti-Arrhythmia Agents; C504573:CYP1A2 protein, human; C510164:CYP3A5 protein, human; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D005424:Flecainide