MDR1 Genotype-Related Pharmacokinetics and Pharmacodynamics.

Abstract

The multidrug resistant transporter MDR1/P-glycoprotein, the gene product of MDR1, is a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding cassette superfamily of membrane transporters. MDR1 acts as an energy-dependent efflux pump that exports its substrates out of cells. MDR1 was originally isolated from resistant tumor cells as part of the mechanism of multidrug resistance, but over the last decade, it has been elucidated that human MDR1 is also expressed throughout the body to confer intrinsic resistance to the tissues by exporting unnecessary or toxic exogeneous substances or metabolites. A number of structurally unrelated drugs are substrates for MDR1, and MDR1 and other transporters are recognized as an important class of proteins for regulating pharmacokinetics and pharmacodynamics. In 2000, Hoffmeyer et al. performed a systemic screening for MDR1 polymorphisms and detected 15 single nucleotide polymorphisms (SNPs). They also indicated that a polymorphism in exon 26 at position 3435 (C3435T), a silent mutation, affected the expression level of MDR1 protein in duodenum, and thereby the intestinal absorption of digoxin. To date, the genotype frequencies of C3435T have been investigated extensively using a larger population and interethnic difference has been elucidated, and a total of 28 SNPs have been found at 27 positions on the MDR1 gene. Clinical studies on MDR1 genotype-related MDR1 expression and pharmacokinetics have also been performed around the world; however, results were not always consistent with Hoffmeyer's report. In this review, published reports are summarized for the future individualization of pharmacotherapy based on MDR1 genotyping. In addition, recent investigations have raised the possibility that MDR1 and related transporters play a fundamental role in regulating apoptosis and immunology, and in fact, there are reports of MDR1-related susceptibility to inflammatory bowel disease, HIV infection and renal cell carcinoma. Herein, these issues are also summarized, and the current status of the knowledge in the area of pharmacogenomics of other transporters is briefly introduced.

MDR1 Gene Polymorphism in Japanese Patients with Schizophrenia and Mood Disorders Including Depression

“…Hoffmeyer et al and Tanabe et al found that 3435 T/T or 2677 T/T, T/A were associated with lower P-gp expression levels in the intestine 21) and placenta, 17) though the opposite results were reported in MDR1 mRNA expression. 22) Sakaeda et al reported that 3435 T/T coding exon 26 produced higher MDR1 mRNA expression on duodenal specimen 22,23) and peripheral blood mononuclear cells stimulated by lipopolysaccharide. 24) These observations suggest that MDR1 polymorphisms for exon also participate the change in P-gp activity on BBB, though the clinical investigation for verapamil penetration into the brain 25) does not support this hypothesis.…”

Effects of Reactive Oxygen Species on Cell Proliferation and Death in HeLa Cells and Its MDR1-Overexpressing Derivative Cell Line.

“…7,8) MDR1 is a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding cassette superfamily, and acts as an energydependent efflux pump that exports substrates out of cells. [9][10][11] Numerous clinical studies have concluded that MDR1 overexpression was associated with a failure of chemotherapy; however, there is no information on the relationship between the effects of oxidative stress on cell proliferation or death and MDR1 expression levels.…”

‘Genetic profiling’ and ovarian cancer therapy (Review)

“…Approximately 25 SNPs for the mdr1 gene were identified (13)(14)(15). However, the most important SNPs in Caucasians are G2677T/A and C3435T as these SNPs have been shown to be involved in P-glycoprotein expression and phenotype (13,16).…”