Genetic Polymorphisms in the ABCB1 Gene and the Effects of Fentanyl in Koreans

Abstract

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.

Molecular Genetics of Variability in Human Pain

“…Based on the patient genotypes of the SNPs listed above, Campa et al (2007) were able to predict patients as being 'strong responders', 'responder' or 'nonresponders' with sensitivity close to 100% and specificity more than 70%. In addition to the aforementioned 3435C4T ABCB1 alleles, 1236C4T and 2677G4T/A protect against the respiratory depressive effects of fentanyl (Park et al, 2006).…”

Transport of Selected PET Radiotracers by Human P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2): An In Vitro Screening

“…Some genetic variants of the ABCB1 and ABCG2 genes are believed to influence the pharmacokinetics of their substrates, as reported for the opiates methadone (2) and fentanyl (3), which are putative P-gp substrates, whose distributions may be influenced by P-gp activity (4). Regional variations in the function of P-gp at the BBB of individuals with neurologic disorders such as epilepsia, Parkinson disease, and Alzheimer disease (1,5) may occur.…”

Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions

“…A number of in vivo studies have concluded that fentanyl is a P-gp substrate while one suggested it is rather an Oatp substrate (136). Clinical results are not in consensus either, with some suggesting P-gp function has a significant role in the pharmacodynamics of fentanyl (131,132), while others suggest otherwise (133,134). Clinical evidence also suggests fentanyl is not an OATP substrate, implying fentanyl may be safely concomitantly administered with OATP substrates or inhibitors (135).…”

“…Another clinical study of 126 patients undergoing spinal anesthesia found certain ABCB1 genotypes were linked with increased fentanyl-induced respiratory depression. Patients with the genotypes 1236TT, 2677TT, and 3435TT were found to have early and profound respiratory depression (65-73% of initial respiratory rate) following intravenous fentanyl administration, suggesting ABCB1 polymorphisms may have important clinical implications in fentanyl safety (132). However, another clinical study of 83 patients also undergoing intravenous fentanyl treatment for spinal anesthesia concluded that ABCB1 polymorphisms had no effect on fentanyl-induced sedation or respiratory depression (133).…”

“…As with morphine, there does not appear to be a clear consensus on the role of ABCB1 polymorphisms in the PK and PD of oxycodone (113)(114)(115), fentanyl (132)(133)(134), or methadone (155-162, 164, 165). The reasons behind this apparent lack of clarity may be complex, and possibly involve the geographic distribution of patients enrolled as well as the polymorphisms selected for investigation.…”