ABSTRACT
Breast cancer resistance protein (BCRP) is a point of interest in drug-drug interaction safety testing. Therefore, a consensus probe that can be applied as victim in multiple experimental settings is of great benefit. Identification of candidates has been driven by the amount and quality of available clinical data, and as a result, drugs such as sulfasalazine and rosuvastatin have been suggested. In this article, the in vitro performance of 5 possible alternatives was evaluated: atorvastatin, chlorothiazide, dantrolene, topotecan, and teriflunomide, and benchmarked against sulfasalazine and rosuvastatin in reference in vitro assays for BCRP drug-drug interaction testing. Based on the results, teriflunomide is proposed as an alternate in vitro BCRP probe.
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Neoplasm Proteins/metabolism , Animals , Biological Transport , Caco-2 Cells , Crotonates/metabolism , Crotonates/pharmacokinetics , Crotonates/pharmacology , Dogs , Drug Interactions , Humans , Hydroxybutyrates , Madin Darby Canine Kidney Cells , Nitriles , Toluidines/metabolism , Toluidines/pharmacokinetics , Toluidines/pharmacologyABSTRACT
We are showing that chlorothiazide, a diuretic, is an ABCG2 substrate. It is a Biopharmaceutics Classification System/Biopharmaceutics Drug Distribution and Classification System (BCS/BDDCS) Class IV drug with low bioavailability. Therefore, we tested if chlorothiazide interacts with major apically located intestinal efflux transporters. Our data show that chlorothiazide is transported by ABCG2 with a Km value of 334.6 µM and does not interact with ABCB1 or ABCC2. The chlorothiazide-ABCG2 interaction results in a vectorial transport in MDCKII-BCRP and Caco-2 cells with efflux ratios of 36 and 8.1 respectively. Inhibition of ABCG2 in Caco-2 cells reduced the efflux ratio to 1.4, suggesting that ABCG2 plays a role in limiting chlorothiazide bioavailability in humans.
Subject(s)
ATP-Binding Cassette Transporters/metabolism , Cell Membrane Permeability , Chlorothiazide/metabolism , Diuretics/metabolism , Enterocytes/metabolism , Neoplasm Proteins/metabolism , Sodium Chloride Symporter Inhibitors/metabolism , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/antagonists & inhibitors , ATP-Binding Cassette Transporters/genetics , Adenosine Triphosphate/antagonists & inhibitors , Adenosine Triphosphate/metabolism , Animals , Biological Transport/drug effects , Caco-2 Cells , Cell Membrane Permeability/drug effects , Dogs , Enterocytes/drug effects , Estrone/analogs & derivatives , Estrone/metabolism , Humans , Intestinal Absorption/drug effects , Kinetics , Madin Darby Canine Kidney Cells , Membrane Transport Modulators/pharmacology , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/genetics , Multidrug Resistance-Associated Proteins/metabolism , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Transport Vesicles/drug effects , Transport Vesicles/metabolismABSTRACT
This study provides evidence that quinidine can be used as a probe substrate for ABCB1 in multiple experimental systems both in vitro and in vivo relevant to the blood-brain barrier (BBB). The combination of quinidine and PSC-833 (valspodar) is an effective tool to assess investigational drugs for interactions on ABCB1. Effects of quinidine and substrate-inhibitor interactions were tested in a membrane assay and in monolayer assays. The authors compared quinidine and digoxin as ABCB1 probes in the in vitro assays and found that quinidine was more potent and at least as specific as digoxin in ATPase and monolayer efflux assays employing MDCKII-MDR1 and the rat brain microcapillary endothelial cell system. Brain exposure to quinidine was tested in dual-/triple-probe microdialysis experiments in rats by assessing levels of quinidine in blood and brain. Comparing quinidine levels in dialysate samples from valspodar-treated and control animals, it is evident that systemic/local administration of the inhibitor diminishes the pumping function of ABCB1 at the BBB, resulting in an increased brain penetration of quinidine. In sum, quinidine is a good probe to study ABCB1 function at the BBB. Moreover, quinidine/PSC-833 is an ABCB1-specific substrate/inhibitor combination applicable to many assay systems both in vitro and in vivo.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B/metabolism , Blood-Brain Barrier/drug effects , Brain/drug effects , Drug Evaluation, Preclinical/methods , Endothelial Cells/drug effects , Endothelium, Vascular/drug effects , High-Throughput Screening Assays , ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors , Animals , Biological Products/analysis , Blood-Brain Barrier/metabolism , Brain/cytology , Brain/metabolism , Cell Line , Chromatography, High Pressure Liquid , Coculture Techniques , Cyclosporins/pharmacology , Digoxin/pharmacology , Dogs , Drug Combinations , Drug Interactions , Endothelial Cells/cytology , Endothelial Cells/metabolism , Endothelium, Vascular/cytology , Endothelium, Vascular/metabolism , Enzyme Inhibitors/pharmacology , Immunosuppressive Agents/pharmacology , Male , Microdialysis , Quinidine/pharmacology , Rats , Rats, WistarABSTRACT
Ivermectin is an antiparasitic drug frequently administered to humans. It has a limited brain exposure that is attributed to the efflux activity of ABCB1/Abcb1. ABCG2/Abcg2 is also a major transporter present in most pharmacologically important barriers. However, interaction of ivermectin with Abcg2 shows species specificity and in many studies was confounded by the masking effect of ABCB1/Abcb1. In this study using cellular and membrane assays we show that ivermectin displays a high-affinity interaction with human ABCG2 with IC(50) values in the 1-1.5 µM range. This interaction may have implications in human ABCG2-mediated drug-drug interactions of ivermectin.
Subject(s)
ATP-Binding Cassette Transporters/antagonists & inhibitors , Antiparasitic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Ivermectin/pharmacology , Neoplasm Proteins/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily G, Member 2 , Biological Transport, Active/drug effects , Cell Line , Cell Membrane/metabolism , Estrone/analogs & derivatives , Estrone/pharmacokinetics , Humans , KineticsABSTRACT
UNLABELLED: Wound infection is a typical, partly preventable complication of cesarean sections. We started extended recording of cesarean section data in October, 2008 as part of our general wound infection surveillance program. AIM: To describe the circumstances and outcomes of the sections and analyze associations between them. METHODS: We analyzed 523 cases over the period October 1, 2008 to September 30, 2009. Variables were assessed using descriptive statistics. Associations between explanatory factors and wound infection were evaluated using logistic regression. RESULTS: Infections (overall rate: 3.6%) were more frequent in younger subjects, those with anemia, subcutaneous hematoma, in pregnancies with meconium stained or purulent amniotic fluid, and decreased to about a third after infection control was tightened. CONCLUSIONS: by being a proxy variable of factors with which wound infection is associated, age is a clinically valuable predictive variable. Good infection control practice is effective in preventing wound infections. The results are consistent with appropriate prescription practices of prophylactic antibiotic use, and with prophylactic measures being effective.
