Genetic polymorphisms in the ABCB1 gene and the effects of fentanyl in Koreans.
P-glycoprotein (PGP) is a polymorphic transporter encoded by the ABCB1 gene that contributes to the access of xenobiotics into the brain. There is no report on associations between genetic polymorphisms in ABCB1 and the clinical effects of fentanyl, although fentanyl may be a substrate of PGP. One hundred and twenty-six (126) unrelated Korean patients under spinal anesthesia with intravenous fentanyl (2.5 microg/kg) were recruited. Clinical effects (bispectral index, respiration rate, and need for oxygen supplementation) were monitored and these were compared between genotypes for three single nucleotide polymorphisms in ABCB1 (1236C>T, 2677G>T/A, and 3435C>T). The allele and genotype frequencies were similar to previous data from Asians; the three major haplotypes, TTT (30%), TGC (24%), and CGC (24%) were expected among nine known haplotypes. During the initial 10 min, there were differences in suppression of respiration rate by fentanyl among the three genotypes (P=0.0933 for 1236C>T; P=0.0941 for 2677G>A/T; P=0.0013 for 3435C>T, repeated-measures analysis of variance), but the differences in bispectral index among genotypes were not observed. Furthermore, patients carrying the linked 3435T and 2677T alleles showed a significant difference in the level of respiratory suppression (P=0.0056); those with genotypes susceptible to fentanyl (1236TT, 2677TT, and 3435TT) showed early (2-3 min) and profound suppression of respiration (65-73% of initial respiration rate) compared with other resistant genotypes (83-85% of initial respiration rate in 1236CC, 2677GG, and 3435CC). Although the need to supply oxygen was not significantly different between genotypes, there was a trend for increased demand by patients carrying both 1236T and 3435T alleles (P=0.0847). In conclusion, our results confirm ABCB1 genotype data for Koreans and suggest that analysis of ABCB1 polymorphisms may have clinical relevance to prevent respiratory suppression by intravenous fentanyl or to anticipate its clinical effects.
Park
H-J
HJ
Department of Anesthesiology, Inha University Hospital, Inha University, Incheon, South Korea.
Shinn
H K
HK
Ryu
S H
SH
Lee
H-S
HS
Park
C-S
CS
Kang
J-H
JH
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000328:Adult; D000368:Aged; D000775:Anesthesia, Spinal; D018686:Anesthetics, Intravenous; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D005283:Fentanyl; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007723:Korea / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D010101:Oxygen Consumption / Q000187:drug effects; D011110:Polymorphism, Genetic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015656:Respiratory Mechanics / Q000187:drug effects
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018686:Anesthetics, Intravenous; D027361:Organic Anion Transporters; D005283:Fentanyl