Very important pharmacogene summary

Hodges, Leslie C.; Markova, Svetlana; Chinn, Leslie W.; Gow, Jason M.; Kroetz, Deanna L.; Klein, Teri E.; Altman, Russ B.

doi:10.1097/fpc.0b013e3283385a1c

Cited by 387 publications

(310 citation statements)

References 165 publications

(222 reference statements)

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“…P-gp recognizes and effluxes a multitude of structurally and biochemically unrelated substrates (cyclic, linear, basic, uncharged, zwitterionic, negatively charged, hydrophobic, aromatic, nonaromatic, amphipathic) that range from a molecular weight of 250 to 4000 (Hodges et al, 2011). The impact of the P-gp mutation on human loperamide PK has been a subject of debate (Benet at al., 2004).…”

Section: Discussionmentioning

confidence: 99%

Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study

Myers

Martinez

et al. 2015

Drug Metab Dispos

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Thirty-three Collies (14 male and 19 female) were used in a doseescalation study to determine the impact of ABCB1 genotype on loperamide pharmacokinetics (PK) and pharmacodynamics (PD). Loperamide was orally administered in four ascending doses (0.01, 0.05, 0.1, or 0.2 mg/kg) over a 4-wk period to fasted Collies. Comparisons were made within each dose to genotype, phenotype, and whether Collies received three (3D) or four (4D) loperamide doses. The 3D and 4D groupings had statistically significant differences in systemic drug exposure (defined by the area under the concentration-versus-time profile estimated from time zero to the last quantifiable drug concentration, AUC 0-last ). In contrast, statistical differences in AUC 0-last only occurred in the comparison between wild-type (WT) Collies versus homozygous mutant (Mut) Collies administered 0.1 mg/kg. Statistical differences in the proportionality relationship were observed when comparing 3D to 4D Collies, and the WT to Mut Collies. Intersubject variability in drug exposure tended to be twice as high between Mut and WT Collies. Associations were observed between systemic drug exposure and ataxia or depression but not between systemic drug exposure and mydriasis or salivation. Thus, Collies expressing the greatest sensitivity to CNS-associated effects of loperamide (Mut) tended to have higher drug exposure compared with those less sensitive to the adverse effects of loperamide. Genotype and phenotype only partially explained differences in loperamide PK and PD, suggesting this relationship may not be straightforward and that other factors need to be considered. Accordingly, the PD and PK of one P-glycoprotein substrate only partially predicted the likelihood of adverse responses to unrelated substrates.

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Section: Discussionmentioning

confidence: 99%

Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study

Myers

Martinez

et al. 2015

Drug Metab Dispos

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“…1 We find some endogenous compounds like amyloid-β, steroids and platelet-activating factor (PAF) 5–7,14 but mainly a very large number of therapeutic drugs (Table 1). 15 However, two other important ABC transporters, Breast Cancer Resistance Protein 1 (BCRP-1) 16 and Multidrug Resistance Protein 1 (MRP-1), 17 have also been implicated in chemotherapeutic resistance with a partially shared substrate specificity with MDR1 (Table 1). Polymorphisms of ABCB1 can also modify the efflux capacities of various substrates.…”

Section: Introductionmentioning

confidence: 99%

MDR1 in immunity: friend or foe?

et al. 2018

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MDR1 is an ATP-dependent transmembrane transporter primarily studied for its role in the detoxification of tissues and for its implication in resistance of tumor cells to chemotherapy treatment. Several studies also report on its expression on immune cells where it plays a protective role from xenobiotics and toxins. This review provides an overview of what is known on MDR1 expression in immune cells in human, and its implications in different pathologies and their treatment options.

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“…One of the most common polymorphisms of ABCB1 gene, related to impaired transport mediated by this protein, is a synonymous mutation C3435T (rs1045642) in exon 26. Polymorphic T allele is associated with more than two times lower P-gp intestinal expression and increased in vivo activity [8,11,12] . Not only its expression, but the affinity of the transporter for various drugs may also be altered [13] .…”

Section: Introductionmentioning

confidence: 99%

“…Clopidogrel is a substrate for permeability glycoprotein (P-gp) [8,9] . In the small intestine, P-gp is located on the enterocyte luminal membrane, and mediates substrate's efflux, thus limiting the absorption [10] .…”

Section: Introductionmentioning

confidence: 99%

P-Glycoprotein Polymorphism C3435T Is Associated with Dose-Adjusted Clopidogrel and 2-Oxo-Clopidogrel Concentration

Stokanović

Nikolić²,

Konstantinović³

et al. 2015

Pharmacology

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Background/Aims: One of the most common polymorphisms of ABCB1 gene, a synonymous mutation C3435T (rs1045642), is associated with increased in vivo activity. The main goal of this study was to determine the association of C3435T polymorphism with clopidogrel and 2-oxo-clopidogrel concentrations in plasma. Methods: The patients were recruited upon acute myocardial infarction diagnosis. They were all tested for ABCB1 C3435T polymorphism. In plasma, drawn 1 h after the drug administration, concentrations of clopidogrel and 2-oxo-clopidogrel were measured using UHPLC-DAD-MS analysis. Results: Due to differences in the maintenance doses, we have calculated the dose-adjusted concentrations of clopidogrel (0.2 ng/ml/mg (0.1-0.4)) and 2-oxo-clopidogrel (2.1 ng/ml/mg (0.5-4.6)). Patients carrying at least one C allele achieved significantly higher serum concentration of clopidogrel (p < 0.001), as well as dose-adjusted clopidogrel (p < 0.001) and 2-oxo-clopidogrel concentrations (p < 0.05). Conclusion: The ABCB1 3435CC genotype is associated with increased clopidogrel and 2-oxo-clopidogrel dose-adjusted concentrations. Therefore, the ABCB1 C3435T genotyping should be one of the parameters taken into account when deciding about the dosing regimen of clopidogrel.

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Very important pharmacogene summary

Cited by 387 publications

References 165 publications

Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study

Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study

MDR1 in immunity: friend or foe?

P-Glycoprotein Polymorphism C3435T Is Associated with Dose-Adjusted Clopidogrel and 2-Oxo-Clopidogrel Concentration

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