The Experts below are selected from a list of 84 Experts worldwide ranked by ideXlab platform
Bart Staels - One of the best experts on this subject based on the ideXlab platform.
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Transcriptional Induction of Rat Liver Apolipoprotein A‐I Gene Expression by Glucocorticoids Requires the Glucocorticoid Receptor and a Labile Cell‐Specific Protein
European journal of biochemistry, 1996Co-Authors: Régis Saladin, Ngoc Vu-dac, Jean-charles Fruchart, Johan Auwerx, Bart StaelsAbstract:Treatment with glucocorticoids increases the concentration of plasma high-density lipoprotein (HDL), which is inversely correlated to the development of atherosclerosis. Previously, we demonstrated that repeated administration of glucocorticoids increases apolipoprotein (apo) A-I gene expression and decreases apoA-II gene expression in rat liver. In the present study, the mechanism of glucocorticoid action on hepatic apoA-I and apoA-II expression was studied. A single injection of rats with dexamethasone increased hepatic apoA-I mRNA levels within 6 h and further increases were observed after 12 h and 24 h. In contrast, liver apoA-II mRNA levels gradually decreased after dexamethasone treatment to less than 25% control levels after 24 h. In rat primary hepatocytes and McARH8994 hepatoma Cells, addition of dexamethasone increased apoA-I mRNA levels in a time-dependent and dose-dependent manner, whereas apoA-II mRNA levels were unchanged. Simultaneous addition of the glucocorticoid antagonist RU486 prevented the increase in apoA-I mRNA levels after dexamethasone treatment, which suggests that the effects of dexamethasone are mediated through the glucocorticoid receptor. Inhibition of transcription by actinomycin D and nuclear-run-on experiments in McARH8994 Cells and primary hepatocytes showed that dexamethasone induced apoA-I, but not apoA-II, gene transcription. Transient-transfection assays in McARH8994 Cells with a chloramphenicol acetyl transferase vector driven by the rat-apoA-I-gene promoter demonstrated that the proximal apoA-I promoter could be induced by dexamethasone, and this effect could be abolished by simultaneous treatment with RU486. However, in COS-1 Cells, apoA-I promoter transcription was not induced by dexamethasone or cotransfected glucocorticoid receptor. In addition, the induction of apoA-I gene transcription by dexamethasone was blocked by the protein-synthesis inhibitor cycloheximide, which suggests the presence of a Labile protein involved in apoA-I gene activation by dexamethasone. In conclusion, our results demonstrate that dexamethasone regulates rat apoA-I, but not apoA-II, gene expression through direct action on the hepatocyte. The induction of apoA-I gene transcription by dexamethasone requires the glucocorticoid receptor and a Labile Cell-specific protein.
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transcriptional induction of rat liver apolipoprotein a i gene expression by glucocorticoids requires the glucocorticoid receptor and a Labile Cell specific protein
FEBS Journal, 1996Co-Authors: Régis Saladin, Jean-charles Fruchart, Johan Auwerx, Ngoc Vudac, Bart StaelsAbstract:Treatment with glucocorticoids increases the concentration of plasma high-density lipoprotein (HDL), which is inversely correlated to the development of atherosclerosis. Previously, we demonstrated that repeated administration of glucocorticoids increases apolipoprotein (apo) A-I gene expression and decreases apoA-II gene expression in rat liver. In the present study, the mechanism of glucocorticoid action on hepatic apoA-I and apoA-II expression was studied. A single injection of rats with dexamethasone increased hepatic apoA-I mRNA levels within 6 h and further increases were observed after 12 h and 24 h. In contrast, liver apoA-II mRNA levels gradually decreased after dexamethasone treatment to less than 25% control levels after 24 h. In rat primary hepatocytes and McARH8994 hepatoma Cells, addition of dexamethasone increased apoA-I mRNA levels in a time-dependent and dose-dependent manner, whereas apoA-II mRNA levels were unchanged. Simultaneous addition of the glucocorticoid antagonist RU486 prevented the increase in apoA-I mRNA levels after dexamethasone treatment, which suggests that the effects of dexamethasone are mediated through the glucocorticoid receptor. Inhibition of transcription by actinomycin D and nuclear-run-on experiments in McARH8994 Cells and primary hepatocytes showed that dexamethasone induced apoA-I, but not apoA-II, gene transcription. Transient-transfection assays in McARH8994 Cells with a chloramphenicol acetyl transferase vector driven by the rat-apoA-I-gene promoter demonstrated that the proximal apoA-I promoter could be induced by dexamethasone, and this effect could be abolished by simultaneous treatment with RU486. However, in COS-1 Cells, apoA-I promoter transcription was not induced by dexamethasone or cotransfected glucocorticoid receptor. In addition, the induction of apoA-I gene transcription by dexamethasone was blocked by the protein-synthesis inhibitor cycloheximide, which suggests the presence of a Labile protein involved in apoA-I gene activation by dexamethasone. In conclusion, our results demonstrate that dexamethasone regulates rat apoA-I, but not apoA-II, gene expression through direct action on the hepatocyte. The induction of apoA-I gene transcription by dexamethasone requires the glucocorticoid receptor and a Labile Cell-specific protein.
Régis Saladin - One of the best experts on this subject based on the ideXlab platform.
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Transcriptional Induction of Rat Liver Apolipoprotein A‐I Gene Expression by Glucocorticoids Requires the Glucocorticoid Receptor and a Labile Cell‐Specific Protein
European journal of biochemistry, 1996Co-Authors: Régis Saladin, Ngoc Vu-dac, Jean-charles Fruchart, Johan Auwerx, Bart StaelsAbstract:Treatment with glucocorticoids increases the concentration of plasma high-density lipoprotein (HDL), which is inversely correlated to the development of atherosclerosis. Previously, we demonstrated that repeated administration of glucocorticoids increases apolipoprotein (apo) A-I gene expression and decreases apoA-II gene expression in rat liver. In the present study, the mechanism of glucocorticoid action on hepatic apoA-I and apoA-II expression was studied. A single injection of rats with dexamethasone increased hepatic apoA-I mRNA levels within 6 h and further increases were observed after 12 h and 24 h. In contrast, liver apoA-II mRNA levels gradually decreased after dexamethasone treatment to less than 25% control levels after 24 h. In rat primary hepatocytes and McARH8994 hepatoma Cells, addition of dexamethasone increased apoA-I mRNA levels in a time-dependent and dose-dependent manner, whereas apoA-II mRNA levels were unchanged. Simultaneous addition of the glucocorticoid antagonist RU486 prevented the increase in apoA-I mRNA levels after dexamethasone treatment, which suggests that the effects of dexamethasone are mediated through the glucocorticoid receptor. Inhibition of transcription by actinomycin D and nuclear-run-on experiments in McARH8994 Cells and primary hepatocytes showed that dexamethasone induced apoA-I, but not apoA-II, gene transcription. Transient-transfection assays in McARH8994 Cells with a chloramphenicol acetyl transferase vector driven by the rat-apoA-I-gene promoter demonstrated that the proximal apoA-I promoter could be induced by dexamethasone, and this effect could be abolished by simultaneous treatment with RU486. However, in COS-1 Cells, apoA-I promoter transcription was not induced by dexamethasone or cotransfected glucocorticoid receptor. In addition, the induction of apoA-I gene transcription by dexamethasone was blocked by the protein-synthesis inhibitor cycloheximide, which suggests the presence of a Labile protein involved in apoA-I gene activation by dexamethasone. In conclusion, our results demonstrate that dexamethasone regulates rat apoA-I, but not apoA-II, gene expression through direct action on the hepatocyte. The induction of apoA-I gene transcription by dexamethasone requires the glucocorticoid receptor and a Labile Cell-specific protein.
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transcriptional induction of rat liver apolipoprotein a i gene expression by glucocorticoids requires the glucocorticoid receptor and a Labile Cell specific protein
FEBS Journal, 1996Co-Authors: Régis Saladin, Jean-charles Fruchart, Johan Auwerx, Ngoc Vudac, Bart StaelsAbstract:Treatment with glucocorticoids increases the concentration of plasma high-density lipoprotein (HDL), which is inversely correlated to the development of atherosclerosis. Previously, we demonstrated that repeated administration of glucocorticoids increases apolipoprotein (apo) A-I gene expression and decreases apoA-II gene expression in rat liver. In the present study, the mechanism of glucocorticoid action on hepatic apoA-I and apoA-II expression was studied. A single injection of rats with dexamethasone increased hepatic apoA-I mRNA levels within 6 h and further increases were observed after 12 h and 24 h. In contrast, liver apoA-II mRNA levels gradually decreased after dexamethasone treatment to less than 25% control levels after 24 h. In rat primary hepatocytes and McARH8994 hepatoma Cells, addition of dexamethasone increased apoA-I mRNA levels in a time-dependent and dose-dependent manner, whereas apoA-II mRNA levels were unchanged. Simultaneous addition of the glucocorticoid antagonist RU486 prevented the increase in apoA-I mRNA levels after dexamethasone treatment, which suggests that the effects of dexamethasone are mediated through the glucocorticoid receptor. Inhibition of transcription by actinomycin D and nuclear-run-on experiments in McARH8994 Cells and primary hepatocytes showed that dexamethasone induced apoA-I, but not apoA-II, gene transcription. Transient-transfection assays in McARH8994 Cells with a chloramphenicol acetyl transferase vector driven by the rat-apoA-I-gene promoter demonstrated that the proximal apoA-I promoter could be induced by dexamethasone, and this effect could be abolished by simultaneous treatment with RU486. However, in COS-1 Cells, apoA-I promoter transcription was not induced by dexamethasone or cotransfected glucocorticoid receptor. In addition, the induction of apoA-I gene transcription by dexamethasone was blocked by the protein-synthesis inhibitor cycloheximide, which suggests the presence of a Labile protein involved in apoA-I gene activation by dexamethasone. In conclusion, our results demonstrate that dexamethasone regulates rat apoA-I, but not apoA-II, gene expression through direct action on the hepatocyte. The induction of apoA-I gene transcription by dexamethasone requires the glucocorticoid receptor and a Labile Cell-specific protein.
Jean-charles Fruchart - One of the best experts on this subject based on the ideXlab platform.
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Transcriptional Induction of Rat Liver Apolipoprotein A‐I Gene Expression by Glucocorticoids Requires the Glucocorticoid Receptor and a Labile Cell‐Specific Protein
European journal of biochemistry, 1996Co-Authors: Régis Saladin, Ngoc Vu-dac, Jean-charles Fruchart, Johan Auwerx, Bart StaelsAbstract:Treatment with glucocorticoids increases the concentration of plasma high-density lipoprotein (HDL), which is inversely correlated to the development of atherosclerosis. Previously, we demonstrated that repeated administration of glucocorticoids increases apolipoprotein (apo) A-I gene expression and decreases apoA-II gene expression in rat liver. In the present study, the mechanism of glucocorticoid action on hepatic apoA-I and apoA-II expression was studied. A single injection of rats with dexamethasone increased hepatic apoA-I mRNA levels within 6 h and further increases were observed after 12 h and 24 h. In contrast, liver apoA-II mRNA levels gradually decreased after dexamethasone treatment to less than 25% control levels after 24 h. In rat primary hepatocytes and McARH8994 hepatoma Cells, addition of dexamethasone increased apoA-I mRNA levels in a time-dependent and dose-dependent manner, whereas apoA-II mRNA levels were unchanged. Simultaneous addition of the glucocorticoid antagonist RU486 prevented the increase in apoA-I mRNA levels after dexamethasone treatment, which suggests that the effects of dexamethasone are mediated through the glucocorticoid receptor. Inhibition of transcription by actinomycin D and nuclear-run-on experiments in McARH8994 Cells and primary hepatocytes showed that dexamethasone induced apoA-I, but not apoA-II, gene transcription. Transient-transfection assays in McARH8994 Cells with a chloramphenicol acetyl transferase vector driven by the rat-apoA-I-gene promoter demonstrated that the proximal apoA-I promoter could be induced by dexamethasone, and this effect could be abolished by simultaneous treatment with RU486. However, in COS-1 Cells, apoA-I promoter transcription was not induced by dexamethasone or cotransfected glucocorticoid receptor. In addition, the induction of apoA-I gene transcription by dexamethasone was blocked by the protein-synthesis inhibitor cycloheximide, which suggests the presence of a Labile protein involved in apoA-I gene activation by dexamethasone. In conclusion, our results demonstrate that dexamethasone regulates rat apoA-I, but not apoA-II, gene expression through direct action on the hepatocyte. The induction of apoA-I gene transcription by dexamethasone requires the glucocorticoid receptor and a Labile Cell-specific protein.
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transcriptional induction of rat liver apolipoprotein a i gene expression by glucocorticoids requires the glucocorticoid receptor and a Labile Cell specific protein
FEBS Journal, 1996Co-Authors: Régis Saladin, Jean-charles Fruchart, Johan Auwerx, Ngoc Vudac, Bart StaelsAbstract:Treatment with glucocorticoids increases the concentration of plasma high-density lipoprotein (HDL), which is inversely correlated to the development of atherosclerosis. Previously, we demonstrated that repeated administration of glucocorticoids increases apolipoprotein (apo) A-I gene expression and decreases apoA-II gene expression in rat liver. In the present study, the mechanism of glucocorticoid action on hepatic apoA-I and apoA-II expression was studied. A single injection of rats with dexamethasone increased hepatic apoA-I mRNA levels within 6 h and further increases were observed after 12 h and 24 h. In contrast, liver apoA-II mRNA levels gradually decreased after dexamethasone treatment to less than 25% control levels after 24 h. In rat primary hepatocytes and McARH8994 hepatoma Cells, addition of dexamethasone increased apoA-I mRNA levels in a time-dependent and dose-dependent manner, whereas apoA-II mRNA levels were unchanged. Simultaneous addition of the glucocorticoid antagonist RU486 prevented the increase in apoA-I mRNA levels after dexamethasone treatment, which suggests that the effects of dexamethasone are mediated through the glucocorticoid receptor. Inhibition of transcription by actinomycin D and nuclear-run-on experiments in McARH8994 Cells and primary hepatocytes showed that dexamethasone induced apoA-I, but not apoA-II, gene transcription. Transient-transfection assays in McARH8994 Cells with a chloramphenicol acetyl transferase vector driven by the rat-apoA-I-gene promoter demonstrated that the proximal apoA-I promoter could be induced by dexamethasone, and this effect could be abolished by simultaneous treatment with RU486. However, in COS-1 Cells, apoA-I promoter transcription was not induced by dexamethasone or cotransfected glucocorticoid receptor. In addition, the induction of apoA-I gene transcription by dexamethasone was blocked by the protein-synthesis inhibitor cycloheximide, which suggests the presence of a Labile protein involved in apoA-I gene activation by dexamethasone. In conclusion, our results demonstrate that dexamethasone regulates rat apoA-I, but not apoA-II, gene expression through direct action on the hepatocyte. The induction of apoA-I gene transcription by dexamethasone requires the glucocorticoid receptor and a Labile Cell-specific protein.
Johan Auwerx - One of the best experts on this subject based on the ideXlab platform.
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Transcriptional Induction of Rat Liver Apolipoprotein A‐I Gene Expression by Glucocorticoids Requires the Glucocorticoid Receptor and a Labile Cell‐Specific Protein
European journal of biochemistry, 1996Co-Authors: Régis Saladin, Ngoc Vu-dac, Jean-charles Fruchart, Johan Auwerx, Bart StaelsAbstract:Treatment with glucocorticoids increases the concentration of plasma high-density lipoprotein (HDL), which is inversely correlated to the development of atherosclerosis. Previously, we demonstrated that repeated administration of glucocorticoids increases apolipoprotein (apo) A-I gene expression and decreases apoA-II gene expression in rat liver. In the present study, the mechanism of glucocorticoid action on hepatic apoA-I and apoA-II expression was studied. A single injection of rats with dexamethasone increased hepatic apoA-I mRNA levels within 6 h and further increases were observed after 12 h and 24 h. In contrast, liver apoA-II mRNA levels gradually decreased after dexamethasone treatment to less than 25% control levels after 24 h. In rat primary hepatocytes and McARH8994 hepatoma Cells, addition of dexamethasone increased apoA-I mRNA levels in a time-dependent and dose-dependent manner, whereas apoA-II mRNA levels were unchanged. Simultaneous addition of the glucocorticoid antagonist RU486 prevented the increase in apoA-I mRNA levels after dexamethasone treatment, which suggests that the effects of dexamethasone are mediated through the glucocorticoid receptor. Inhibition of transcription by actinomycin D and nuclear-run-on experiments in McARH8994 Cells and primary hepatocytes showed that dexamethasone induced apoA-I, but not apoA-II, gene transcription. Transient-transfection assays in McARH8994 Cells with a chloramphenicol acetyl transferase vector driven by the rat-apoA-I-gene promoter demonstrated that the proximal apoA-I promoter could be induced by dexamethasone, and this effect could be abolished by simultaneous treatment with RU486. However, in COS-1 Cells, apoA-I promoter transcription was not induced by dexamethasone or cotransfected glucocorticoid receptor. In addition, the induction of apoA-I gene transcription by dexamethasone was blocked by the protein-synthesis inhibitor cycloheximide, which suggests the presence of a Labile protein involved in apoA-I gene activation by dexamethasone. In conclusion, our results demonstrate that dexamethasone regulates rat apoA-I, but not apoA-II, gene expression through direct action on the hepatocyte. The induction of apoA-I gene transcription by dexamethasone requires the glucocorticoid receptor and a Labile Cell-specific protein.
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transcriptional induction of rat liver apolipoprotein a i gene expression by glucocorticoids requires the glucocorticoid receptor and a Labile Cell specific protein
FEBS Journal, 1996Co-Authors: Régis Saladin, Jean-charles Fruchart, Johan Auwerx, Ngoc Vudac, Bart StaelsAbstract:Treatment with glucocorticoids increases the concentration of plasma high-density lipoprotein (HDL), which is inversely correlated to the development of atherosclerosis. Previously, we demonstrated that repeated administration of glucocorticoids increases apolipoprotein (apo) A-I gene expression and decreases apoA-II gene expression in rat liver. In the present study, the mechanism of glucocorticoid action on hepatic apoA-I and apoA-II expression was studied. A single injection of rats with dexamethasone increased hepatic apoA-I mRNA levels within 6 h and further increases were observed after 12 h and 24 h. In contrast, liver apoA-II mRNA levels gradually decreased after dexamethasone treatment to less than 25% control levels after 24 h. In rat primary hepatocytes and McARH8994 hepatoma Cells, addition of dexamethasone increased apoA-I mRNA levels in a time-dependent and dose-dependent manner, whereas apoA-II mRNA levels were unchanged. Simultaneous addition of the glucocorticoid antagonist RU486 prevented the increase in apoA-I mRNA levels after dexamethasone treatment, which suggests that the effects of dexamethasone are mediated through the glucocorticoid receptor. Inhibition of transcription by actinomycin D and nuclear-run-on experiments in McARH8994 Cells and primary hepatocytes showed that dexamethasone induced apoA-I, but not apoA-II, gene transcription. Transient-transfection assays in McARH8994 Cells with a chloramphenicol acetyl transferase vector driven by the rat-apoA-I-gene promoter demonstrated that the proximal apoA-I promoter could be induced by dexamethasone, and this effect could be abolished by simultaneous treatment with RU486. However, in COS-1 Cells, apoA-I promoter transcription was not induced by dexamethasone or cotransfected glucocorticoid receptor. In addition, the induction of apoA-I gene transcription by dexamethasone was blocked by the protein-synthesis inhibitor cycloheximide, which suggests the presence of a Labile protein involved in apoA-I gene activation by dexamethasone. In conclusion, our results demonstrate that dexamethasone regulates rat apoA-I, but not apoA-II, gene expression through direct action on the hepatocyte. The induction of apoA-I gene transcription by dexamethasone requires the glucocorticoid receptor and a Labile Cell-specific protein.
Zvi Ioav Cabantchik - One of the best experts on this subject based on the ideXlab platform.
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Labile iron in Cells and body fluids: physiology, pathology, and pharmacology.
Frontiers in pharmacology, 2014Co-Authors: Zvi Ioav CabantchikAbstract:In living systems iron appears predominantly associated with proteins, but can also be detected in forms referred as Labile iron, which denotes the combined redox properties of iron and its amenability to exchange between ligands, including chelators. The Labile Cell iron (LCI) composition varies with metal concentration and substances with chelating groups but also with pH and the redox potential. Although physiologically in the lower µM range, LCI plays a key role in Cell iron economy as cross-roads of metabolic pathways. LCI levels are continually regulated by an iron-responsive machinery that balances iron uptake versus deposition into ferritin. However, LCI rises aberrantly in some Cell types due to faulty Cell utilization pathways or infiltration by pathological iron forms that are found in hemosiderotic plasma. As LCI attains pathological levels, it can catalyze reactive O species (ROS) formation that, at particular threshold, can surpass Cellular anti-oxidant capacities and seriously damage its constituents. While in normal plasma and interstitial fluids, virtually all iron is securely carried by circulating transferrin (that renders iron essentially non-Labile), in systemic iron overload (IO), the total plasma iron binding capacity is often surpassed by a massive iron influx from hyperabsorptive gut or from erythrocyte overburdened spleen and/or liver. As plasma transferrin approaches iron saturation, Labile plasma iron (LPI) emerges in forms that can infiltrate Cells by unregulated routes and raise LCI to toxic levels. Despite the limited knowledge available on LPI speciation in different types and degrees of iron overload, LPI measurements can be and are in fact used for identifying systemic IO and for initiating/adjusting chelation regimens to attain full-day LPI protection. A recent application of Labile iron assay is the detection of Labile components in iv iron formulations per se as well as in plasma (LPI) following parenteral iron administration
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Deferasirox (Exjade®, ICL670): A Journey into Labile Iron Centers of Living Cardiomyocytes.
Blood, 2005Co-Authors: Zvi Ioav Cabantchik, Hava Glickstein, Abraham M. Konijn, Chaim Hershko, Gabriela Link, Hanspeter NickAbstract:Introduction and Aims: Iron toxicity that prevails in iron overload is associated with forms of Labile Cell iron (LCI) that appear in tissues such as heart, endocrine glands and liver. The primary goal of chelation is to reduce LCI appearance by preventing the entry of Labile plasma iron into Cells and by chelating LCI. The present study was aimed at evaluating the capacity of the novel oral iron chelator deferasirox (a) to access cardiomyocytes and chelate LCI in the Cell organelles harboring Labile iron and thereby prevent its involvement in reactive oxidant species (ROS) formation and (b) to reduce the Cell iron load by extraction of Labile and accumulated iron. Methods: LCI pools were revealed by fluorescence microscopy imaging using novel fluorescent iron sensors addressed to various organelles (cytosol, nucleus, mitochondria and endosomeslysosomes) via specific peptide target sequences. Resident or imported Labile iron binds the fluorescence metal sensor and quench its fluorescence. The chelator’s capacity to restore quenched fluorescence in a given Cell compartment is indicative of its permeation and chelating potential, which is also assessed with ROS-sensitive probes targeted to cytosol or mitochondria ( Glickstein et al 2005, Blood In press). Chelator-mediated extraction of Cell iron was assessed in cardiomyocytes from neonatal rats or murine H9C2 Cells preincubated with 360μM 59 Fe-ferric ammonium citrate for 3 h or 24 h (representing respectively radiolabelled LCI=RLCI or stored iron=RSI). Iron extraction was followed as Cell iron retention following 0.5–24 h treatment with chelators in culture medium (with 20% fetal calf serum ≡ 1% albumin or with 4% bovine serum albumin). Results and Discussion: In situ fluorescence LCI tracing studies indicate that LCI chelation by up to 100 μM deferoxamine (DFO) (x10 higher than normally attained in plasma during infusion) demanded incubation times >1 h. Conversely, the relatively smaller and more lipophilic deferasirox at 50–100 μM demonstrably gained access to all LCI pools associated with organelles following 20′–30′ incubation in serum-free medium and 30′–60′ in serum-containing medium (note: deferasirox reaches clinically C max and trough plasma levels of approximately 100 μM and 20 μM respectively with daily doses of 20 mg/kg). Following 6 h treatment with chelator in serum-containing medium, LCI (measured as RLCI) was 15 and 60% reduced by 20 and 100 μM DFO respectively, and 15 and 34% reduced by 20 and 100 μM deferasirox, respectively. On the other hand, the reduction in mostly stored RSI with 20 and 100 μM chelator was 5 and 45% for DFO and 0 and 20% by deferasirox, respectively. Conclusions: At drug concentrations equivalent to those attained in plasma with a single daily drug intake, ie 50–100 μM: (a) deferasirox gains relatively fast entry into cardiomyocytes and their intraCellular compartments, scavenges LCI and attenuates ROS formation; (b) exit of the (deferasirox) 2 -Fe chelates formed from LCI pools (RLCI) by added drug is relatively slower than entry of the free drug, but evident within 1–3 h even at 20 μM drug concentrations (equivalent to trough plasma levels).
