Knockdown of caveolin-1 decreases activity of breast cancer resistance protein (BCRP/ABCG2) and increases chemotherapeutic sensitivity.

The ATP-binding cassette transporter breast cancer resistance protein (BCRP/ABCG2) is supposed to be a major determinant of the multidrug resistance phenotype of tumors by extruding chemically diverse cytostatic drugs out of tumor cells. BCRP physically and possibly also functionally interacts with caveolin-1 (CAV1, encoded by Cav1), an integral membrane protein of lipid rafts important for signal transduction and membrane trafficking. Moreover, Cav1 is linked to an aggressive phenotype of cancer cells in various tumors.

Successful strategy to improve the specificity of electronic statin-drug interaction alerts.

Purpose: A considerable weakness of current clinical decision support systems managing drug-drug interactions (DDI) is the high incidence of inappropriate alerts. Because DDI-induced, dose-dependent adverse events can be prevented by dosage adjustment, corresponding DDI alerts should only be issued if dosages exceed safe limits. We have designed a logical framework for a DDI alert-system that considers prescribed dosage and retrospectively evaluates the impact on the frequency of statin-drug interaction alerts.

Induction of multiple drug transporters by efavirenz.

Efavirenz, an important component of human immunodeficiency virus 1 (HIV-1) therapy, causes substantial drug interactions as an inducer of cytochromes and the transporter ABCB1. So far its effect on the expression of other transporters is unknown. We therefore investigated the effect of long-term exposure of cells to efavirenz on expression of a large number of important drug transporters and on cell proliferation as a surrogate of intracellular availability.

Expression and activity of P-glycoprotein (MDR1/ABCB1) in peripheral blood mononuclear cells from patients with anorexia nervosa compared with healthy controls.

Objective: Pharmacotherapeutic strategies for treatment of anorexia nervosa (AN) are characterized by limited success. Some drugs used (antipsychotics, selective serotonin reuptake inhibitors) are transported by P-glycoprotein (P-gp), a transporter with major impact on pharmacokinetics of substrate drugs. Biochemical alterations seen in AN patients could lead to increased expression and/or activity of P-gp and therefore to diminished access of drugs to the brain.

Plasma LDL cholesterol has no impact on P-glycoprotein (MDR1/ABCB1) activity in human peripheral blood mononuclear cells.

Several studies have demonstrated that the adenosine triphosphate-binding cassette transporter P-glycoprotein (P-gp) is at least partly located in cholesterol- and sphingolipid-enriched parts of the plasma membrane called "lipid rafts" and that modification of cellular cholesterol content has an impact on the activity of P-gp in vitro and ex vivo. Cholesterol modulation in vitro does not closely reflect the in vivo situation. The aim of our study was therefore to investigate whether differences in individual plasma low-density lipoprotein (LDL) cholesterol levels in humans have an impact on cholesterol content in peripheral blood mononuclear cells (PBMCs) and thereby on individual activity of P-gp.

Localization of the human breast cancer resistance protein (BCRP/ABCG2) in lipid rafts/caveolae and modulation of its activity by cholesterol in vitro.

Breast cancer resistance protein (BCRP/ABCG2) is an active efflux pump that belongs to the ATP-binding cassette (ABC) transporter family. It is located in various tissues involved in drug absorption, distribution, and elimination and plays an important role in multidrug resistance. For P-glycoprotein, another member of the ABC transporter family, it is well established that it is at least partly located in cholesterol and sphingolipid-enriched domains of the plasma membrane called "lipid rafts" and that the composition of the membrane lipids may modulate its efflux activity.

Comparison of the inhibitory activity of anti-HIV drugs on P-glycoprotein.

Human immunodeficiency virus 1 (HIV-1) infections are treated with HIV-protease inhibitors (PIs), nucleoside (NRTIs), non-nucleoside (NNRTIs), and nucleotide reverse transcriptase inhibitors (NtRTIs). The combined administration of antiretrovirals improves patient outcomes while increasing the likelihood of drug interactions. Indeed, as substrates, inhibitors, and occasionally also inducers of P-glycoprotein (P-gp) PIs may substantially alter the pharmacokinetics of co-administered drugs.

Modulation of human BCRP (ABCG2) activity by anti-HIV drugs.

Objectives: The safety and effectiveness of highly active antiretroviral therapy (HAART) is challenged by viral resistance to antiretrovirals and the frequent occurrence of drug interactions which may limit the access of these drugs to the target sites. In particular, drug distribution and elimination may be modified by active efflux transporters. While P-glycoprotein is well evaluated in this regard, the interaction of antiretrovirals with the ABC transporter BCRP (ABCG2) is far from being elucidated.