The MDR1 (ABCB1) Gene Polymorphism and its Clinical Implications

Abstract

There has been an increasing appreciation of the role of drug transporters in the pharmacokinetic and pharmacodynamic profiles of certain drugs. Among various drug transporters, P-glycoprotein, the MDR1 gene product, is one of the best studied and characterised. P-glycoprotein is expressed in normal human tissues such as liver, kidney, intestine and the endothelial cells of the blood-brain barrier. Apical (or luminal) expression of P-glycoprotein in these tissues results in reduced drug absorption from the gastrointestinal tract, enhanced drug elimination into bile and urine, and impeded entry of certain drugs into the central nervous system. The clinical relevance of P-glycoprotein depends on the localisation in human tissues (i.e. vectorial or directional movement), the therapeutic index of the substrate drug and the inherent inter- and intra-individual variability. With regard to the variability, polymorphisms of the MDR1 gene have recently been reported to be associated with alterations in disposition kinetics and interaction profiles of clinically useful drugs, including digoxin, fexofenadine, ciclosporin and talinolol. In addition, polymorphism may play a role in patients who do not respond to drug treatment. Moreover, P-glycoprotein is an important prognostic factor in malignant diseases, such as tumours of the gastrointestinal tract.A growing number of preclinical and clinical studies have demonstrated that polymorphism of the MDR1 gene may be a factor in the overall outcome of pharmacotherapy for numerous diseases. We believe that further understanding the physiology and biochemistry of P-glycoprotein with respect to its genetic variations will be important to establish individualised pharmacotherapy with various clinically used drugs.

Drug transporters in pharmacokinetics

“…As with the detoxification enzymes of phase I and phase II, these carriers are subject to postnatal development in neonates (Gao et al 2004), and regulation and induction by diseases may occur (Trauner and Boyer 2003;Kullak-Ublick et al 2004). With the availability of cloned carrier genes, pharmacogenomics of drug transporters have recently been the subject of pharmacological and clinical research (Tirona et al 2001;Tirona and Kim 2002;Ieiri et al 2004). …”

“…There are reports addressing pharmacokinetic consequences related to MDR1 polymorphism (Hoffmeyer et al 2000;Drescher et al 2002Drescher et al , 2003Ieiri et al 2004) and OATP-polymorphisms (Tirona et al 2001;Nozawa et al 2002;König et al 2006). A frequent polymorphism of phase 4 MDR1 carrier occurring in about 12% of patients is the homozygous C3435T exchange.…”

Effect of Anticholinergic Use for the Treatment of Overactive Bladder on Cognitive Function in Postmenopausal Women

“…Furthermore, trospium chloride is a known P-glycoprotein ligand and is actively removed from the central nervous system via efflux. [30] There are abundant data demonstrating cognitive effects of non-selective anticholinergics that do cross the BBB. [9,17,31] However, there is less direct evidence of whether trospium chloride exerts these effects due to its unique properties.…”

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

“…has high clinical relevance in drug therapy and the impact of genetic polymorphisms of ABCB1 on drug disposition as well as drug efficacy has been studied extensively and covered in multiple reviews [10,12,[46][47][48][86][87][88][89][90][91][92]. Overall, more than 50 polymorphisms, insertions/deletions and changes in the promoter region have been reported for ABCB1 encoding MDR1 [12,48,93].…”