Journal Article10.1067/MCP.2001.114164
Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects.
Ingolf Cascorbi,Thomas Gerloff,Andreas Johne,Christian Meisel,Sven Hoffmeyer,Matthias Schwab,Elke Schaeffeler,Eichelbaum Michel,Ulrich Brinkmann,Ivar Roots +9 more
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TL;DR: P‐glycoprotein, the gene product of MDR1, confers multidrug resistance against antineoplastic agents but also plays an important role in the bioavailability of common drugs in medical treatment.
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Abstract: Background
P-glycoprotein, the gene product of MDR1, confers multidrug resistance against antineoplastic agents but also plays an important role in the bioavailability of common drugs in medical treatment. Various polymorphisms in the MDR1 gene were recently identified. A silent mutation in exon 26 (C3435T) was correlated with intestinal P-glycoprotein expression and oral bioavailability of digoxin.
Objective
We wanted to establish easy-to-use and cost-effective genotyping assays for the major known MDR1 single nucleotide polymorphisms and study the allelic frequency distribution of the single nucleotide polymorphisms in a large sample of volunteers.
Methods
In this study, the distribution of the major MDR1 alleles was determined in 461 white volunteers with the use of polymerase chain reaction and restriction fragment length polymorphism.
Results
Five amino acid exchanges were found with allelic frequencies of 11.2% for Asn21Asp and 5.5% for Ser400Asn. Strikingly, in exon 21 three variants were discovered at the same locus: 2677G (56.4%), 2677T (41.6%), and 2677A (1.9%), coding for 893Ala, Ser, or Thr. A novel missense Gln1107Pro mutation was found in two cases (0.2%). The highest frequencies were observed for intronic and silent polymorphisms; C3435T occurred in 53.9% of the subjects heterozygously, and 28.6% of individuals were homozygous carriers of 3435T/T with functionally restrained P-glycoprotein.
Conclusion
This study provides the first analysis of MDR1 variant genotype distribution in a large sample of white subjects. It gives a basis for large-scale clinical investigations on the functional role of MDR1 allelic variants for bioavailability of a substantial number of drugs.
Clinical Pharmacology & Therapeutics (2001) 69, 169–174; doi: 10.1067/mcp.2001.114164
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Citations
•Journal Article
MDR1 Gene Polymorphisms Affect Therapy Outcome in Acute Myeloid Leukemia Patients
Thomas Illmer,Ulrich Schuler,Christian Thiede,Ute I. Schwarz,Richard B. Kim,Sebastian Gotthard,Daniel Freund,Ulrike Schäkel,Gerhard Ehninger,Markus Schaich +9 more
TL;DR: Analysis of acute myeloid leukemia patients investigated for somatic genotypes of the three most frequent single nucleotide polymorphisms (SNPs) in exons 12, 21, and 26 indicates that allelic variants of the MDR1 gene may influence therapy outcome by additional mechanisms, different from P-gp expression on acute myELoid leukemia blasts.
264
Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients.
Norihiko Tsuchiya,Shigeru Satoh,Hitoshi Tada,Zhenhua Li,Chikara Ohyama,Kazunari Sato,Toshio Suzuki,Tomonori Habuchi,Tetsuro Kato +8 more
TL;DR: Kidney transplant recipients with the CYP3A5 *1 allele required a higher daily tacrolimus dose compared with those with the cytochrome P450 3A5*3/*3 genotype to maintain both the target trough level and AUC0–12, suggesting that this polymorphism is useful for determining the appropriate dose of tacolimus.
261
Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature
Stefan Wolking,Elke Schaeffeler,Elke Schaeffeler,Holger Lerche,Matthias Schwab,Anne T. Nies,Anne T. Nies +6 more
TL;DR: The effect of ABCB1 variation on P-glycoprotein expression (messenger RNA and protein expression) and/or activity in various tissues appears to be small and 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 rareABCB1 variants and their potential consequences for effect sizes.
253
The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans.
TL;DR: This review discusses the currently available data on the influence of MDR1 polymorphisms on P-glycoprotein tissue expression, drug disposition, treatment outcome and disease risk.
249
Genetic predictors of the clinical response to opioid analgesics: Clinical utility and future perspectives
TL;DR: This review uses a candidate gene approach to identify possible pharmacogenetic modulators of opioid therapy, and discusses these modulators together with demonstrated genetic causes for the variability in clinical effects of opioids.
245
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