ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research.
The product of the ABCB1 gene, P-glycoprotein (PGP), is a transmembrane active efflux pump for a variety of drugs. It is a putative mechanism of multidrug resistance in a range of diseases. It is postulated that ABCB1 polymorphisms contribute to variability in PGP function, and that therefore multidrug resistance is, at least in part, genetically determined. However, studies of ABCB1 genotype or haplotype and PGP expression, activity or drug response have produced inconsistent results. This critical review of ABCB1 genotype and PGP function, including mRNA expression, PGP-substrate drug pharmacokinetics and drug response, highlights methodological limitations of existing studies, including inadequate power, potential confounding by co-morbidity and co-medication, multiple testing, poor definition of disease phenotype and outcomes, and analysis of multiple drugs that might not be PGP substrates. We have produced recommendations for future research that will aid clarification of the association between ABCB1 genotypes and factors related to PGP activity.
Leschziner
G D
GD
Division of Neurosciences, Imperial College, London, UK. gl1@sanger.ac.uk
Andrew
T
T
Pirmohamed
M
M
Johnson
M R
MR
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000502:physiology*; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D000928:Antidepressive Agents / Q000009:adverse effects; D018791:CD4 Lymphocyte Count; D004077:Digoxin / Q000493:pharmacokinetics; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D027361:Organic Anion Transporters / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D000928:Antidepressive Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D027361:Organic Anion Transporters; D012333:RNA, Messenger; D004077:Digoxin