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 lg/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 (1236C4T, 2677G4T/A, and 3435C4T). 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 ¼ 0.0933 for 1236C4T; P ¼ 0.0941 for 2677G4A/T; P ¼ 0.0013 for 3435C4T, 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 ¼ 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 ¼ 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. P-glycoprotein (PGP), a member of the superfamily of adenosine triphosphate-binding cassette (ABC) transporters, is encoded by the multidrug resistance gene ABCB1 and is an integral membranous protein that actively pumps substrates out of the intracellular compartment. PGP is produced in numerous normal tissues including the gastrointestinal tract, blood–brain barrier, and other barrier tissues involved in the disposition of xenobiotics. 1–5 The abundant expression of PGP in brain capillary endothelial cells might contribute to the limited access of xenobiotics into the central nervous system. Using well-known PGP substrates and/or inhibitors, many investigators presented evidences of which PGP plays an important role in distribution of xenobiotics into the brain. In those experiments using PGP-deficient mdr1