Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

Abstract

ATP-binding cassette transporter B1 (ABCB1; P-glycoprotein; multidrug resistance protein 1) is an adenosine triphosphate (ATP)-dependent efflux transporter located in the plasma membrane of many different cell types. Numerous structurally unrelated compounds, including drugs and environmental toxins, have been identified as substrates. ABCB1 limits the absorption of xenobiotics from the gut lumen, protects sensitive tissues (e.g. the brain, fetus and testes) from xenobiotics and is involved in biliary and renal secretion of its substrates. In recent years, a large number of polymorphisms of the ABCB1 [ATP-binding cassette, sub-family B (MDR/TAP), member 1] gene have been described. The variants 1236C>T (rs1128503, p.G412G), 2677G>T/A (rs2032582, p.A893S/T) and 3435C>T (rs1045642, p.I1145I) occur at high allele frequencies and create a common haplotype; therefore, they have been most widely studied. This review provides an overview of clinical studies published between 2002 and March 2015. In summary, the effect of ABCB1 variation on P-glycoprotein expression (messenger RNA and protein expression) and/or activity in various tissues (e.g. the liver, gut and heart) appears to be small. Although polymorphisms and haplotypes of ABCB1 have been associated with alterations in drug disposition and drug response, including adverse events with various ABCB1 substrates in different ethnic populations, the results have been majorly conflicting, with limited clinical relevance. Future research activities are warranted, considering a deep-sequencing approach, as well as well-designed clinical studies with appropriate sample sizes to elucidate the impact of rare ABCB1 variants and their potential consequences for effect sizes.

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

“…ABCB1 (also known as multidrug resistance protein 1 (MDR1), P-glycoprotein 1, abbreviated as P-gp), a member of ABC transporters family, is expressed at major physiological barriers, such as intestinal epithelium, the canalicular membrane of liver cells, kidney proximal tubule epithelial cells, blood-brain barrier and blood-testis barrier, 42,43 where it exhibits protective and excretory functions. 44 Mutations in ABCB1 have been associated with changes in drug disposition, sensitivity and toxicity. 44 In our previous study, ABCB1 polymorphism was found to be correlated with Gefitinib skin toxicity.…”

“…44 Mutations in ABCB1 have been associated with changes in drug disposition, sensitivity and toxicity. 44 In our previous study, ABCB1 polymorphism was found to be correlated with Gefitinib skin toxicity. 45 We, for the first time, examined the association of ABCB1 rs2235040 CT genotype with periorbital oedema in GIST patients treated with Imatinib, finding it a valuable protective factor in predicting this toxicity.…”

Sphingolipid abnormalities in cancer multidrug resistance: Chicken or egg?

“…Since many of these transcription factors are altered by stress signals, ABCB1 is highly susceptible to upregulation during a stress response. ABCB1 expression can also be modified by single nucleotide polymorphisms (SNPs) [91, 92], which play a very important role in the context of cancer therapy, as well as by gene rearrangements [93], mutations [82, 94], epigenetic regulation [95, 96] and post-translational mechanisms [97]. …”

The importance of drug transporter characterization to precision medicine

“…Respective warnings are included in labels of several drugs, which are ABCB1 substrates. To what extent genetic variants in the ABCB1 gene affect clinical drug response is still inconclusive because study results are in part controversial and/or do not provide sufficient evidence to affect treatment decisions [3]. Therefore, further large-scale studies are warranted to determine the relevance of ABCB1 genetics to precision medicine.…”

“…The SLC superfamily comprises uptake as well as efflux transporters [2]. In contrast, members of the ABC transporter family are predominantly efflux transporters [3]. Interindividual variability of SLC and ABC transporter expression and function thus contributes to differences in treatment efficacy or the occurrence of adverse drug reactions (ADRs).…”