Clin Pharmacokinet. Epub Jun Drug Metab Dispos. Highlighted elements will appear in red. Show In Black and White Clear. Understanding the basis of such variations, i. In children with nephrotic syndrome, large inter-individual variability is present in the course of disease, and efficacy and side effects of glucocorticoids. As the variable response to glucocorticoids in patients with nephrotic syndrome cannot completely be attributed to the disease histology, it is difficult to predict the response based on clinical observations alone.
For nephrotic syndrome, research on the impact of genetic polymorphisms on steroid response and susceptibility to steroid-related toxicities is limited [ 19 ]. For a few other diseases, however, pharmacogenetics has already been implemented in clinical practice [ 66 , 67 ].
Furthermore, in the field of pediatric nephrology, new guidelines on tacrolimus dosing recommend involvement of CYP3A5 genotyping to optimize the immunosuppressive treatment of the individual transplant patients [ 68 ]. In line with the aforementioned examples, we believe that the involvement of pharmacogenetics in the work-up of nephrotic syndrome patients as well might be beneficial, preventing exposure to ineffective drug courses and minimizing drug toxicity.
As the mechanism of action of glucocorticoids involves numerous receptors, enzymes, and proteins, a variety of potential targets of genetic polymorphisms may be present.
Although limited evidence is available, an overview of previously conducted studies on pharmacogenetics of prednisone and prednisolone in patients with nephrotic syndrome is provided below. A summary of the mechanisms and most important results is provided for the targets involved.
Effects of gene polymorphisms affecting glucocorticoid targets in nephrotic syndrome patients. Effects of gene polymorphisms affecting glucocorticoid pharmacokinetics in nephrotic syndrome patients. Therefore, the hypothesis is that genetic alterations in the gene encoding for the GR receptor may account for some degree of inter-individual variability in the glucocorticoid response and steroid-related toxicity in individuals [ 88 ]. In contrast, the polymorphisms NS rs and BC1I rs are associated with an increased sensitivity to glucocorticoids [ 88 , 89 ].
Increased glucocorticoid sensitivity due to a genetic polymorphism might also be associated with increased susceptibility to steroid-related toxicities. Previously, Eipel et al.
To our knowledge, the role of genetic polymorphisms in the GR gene in susceptibility of steroid-related toxicities has only been investigated in patients with nephrotic syndrome in one study.
Teeninga et al. To date, a few studies investigated the role of NR3C1 polymorphisms on the glucocorticoid response in pediatric patients with nephrotic syndrome [ 69 — 72 , 92 , 93 ]. Components of the glucocorticoid heterocomplex are essential to keep the GR in the correct folding for hormone binding and prevent nuclear localization of unoccupied GRs.
Abnormalities in the chaperones and co-chaperones that make up the heterocomplex may contribute to decreased glucocorticoid responsiveness, as the integrity of the GR heterocomplex is required for optimal ligand binding and subsequent activation of the transcriptional response. For several diseases, which are treated with glucocorticoids, including nephrotic syndrome, altered levels of chaperone protein hsp90 were found in peripheral blood mononuclear cells from individuals with a steroid-resistant course of disease [ 94 — 96 ].
Interestingly, this could also hold true for nephrotic syndrome patients as well. Recently, one study was published on the potential role of FKBP5 polymorphism rs in a small group of pediatric nephrotic syndrome patients showing a higher frequency in patients with a steroid-dependent nephrotic syndrome [ 73 ].
Nuclear translocation receptors, known as importins, play a significant role in the mechanism of glucocorticoid action. In children with asthma, polymorphisms encoding the IPO13 gene resulted in increased sensitivity for glucocorticoids, which was most likely due to the increased availability of glucocorticoids in the nucleus [ 98 ].
The role of genetic polymorphisms in the gene encoding for IPO13 in patients with nephrotic syndrome is unknown [ 19 ]. To date, the exact underlying pathophysiological mechanisms of nephrotic syndrome are still unknown. One of the hypotheses is that nephrotic syndrome is associated with an immunoregulatory imbalance between T helper subtype 1 Th1 and T helper subtype 2 Th2 cells.
Cytokines produced by the T helper cells play a role as mediators of inflammation. The evidence for genetic polymorphisms in the cytokine genes in patients with nephrotic syndrome is, however, limited.
Minimal change nephrotic syndrome is associated with atopy and IgE production [ 99 ]. T helper subtype 2 cytokines, such as IL-4 and IL, are known to be involved in the development of atopy. Several studies have been conducted to investigate the role of polymorphisms in the genes coding for IL-4, IL-6, and IL in pediatric patients with nephrotic syndrome [ 74 — 76 , — ].
The IL-4 polymorphism rs was associated with nephrotic syndrome and an increased risk of steroid resistance [ 74 — 76 ]. Furthermore, previous research conducted by Jafar et al. No significant association was found between the IL gene polymorphisms and disease susceptibility or steroid responsiveness [ 71 , , ].
An important pro-inflammatory cytokine is macrophage migration inhibitory factor MIF. MIF has the unique ability to override the inhibitory effects of glucocorticoids on the immune system. Due to its regulatory properties, MIF is considered a critical mediator in various immune and inflammatory diseases.
Several studies have been conducted to investigate the potential role of this genetic polymorphism in the gene encoding for MIF in patients with nephrotic syndrome [ 71 , 79 — 81 , , ]. A meta-analysis conducted by Tong et al. GLCCI1 was initially described as a thymocyte-specific transcript that is rapidly upregulated in response to dexamethasone treatment [ ]. Knockdown of the GLCCI1 gene resulted in disruption of the glomerular permeability filter and podocyte foot process effacement.
A genome-wide association study in patients with asthma showed a significant association between the genetic polymorphism rs of the GLCCI1 gene and a decreased response to glucocorticoid inhalation therapy [ ]. In contrast, two studies in pediatric nephrotic syndrome patients could not confirm the association between this specific polymorphism and steroid responsiveness in patients with nephrotic syndrome [ 71 , ].
P-glycoprotein is an efflux pump encoded by the multidrug resistance protein 1 gene MDR1. Glucocorticoids are known substrates for P-glycoprotein and may also induce P-glycoprotein expression [ 52 , ]. In the kidney, P-glycoprotein is expressed in the brush border membrane of proximal tubular epithelial cells. Increased expression of P-glycoprotein results in decreased intracellular drug concentrations and may consequently decrease treatment response.
Previous research has shown higher expression of MDR1 and increased P-glycoprotein activity in children with steroid-resistant nephrotic syndrome [ , ]. To date, approximately 50 genetic polymorphisms have been reported in the MDR1 gene.
The interpretation of the influence of the genetic polymorphisms on P-glycoprotein expression, however, is unresolved and may vary depending on tissue type, pathological status, and ethnicity [ ]. A recent systematic review on pharmacogenetics and adverse drug reactions in pediatric oncology patients indicated protective effects from two genetic polymorphisms of the MDR1 gene in methotrexate- and vincristine-related neurotoxicity in pediatric ALL patients [ ].
In nephrotic syndrome patients, however, no studies have been conducted to investigate the potential role of genetic polymorphisms in the MDR1 gene in steroid-related toxicities. Several studies have been conducted to evaluate the association of P-glycoprotein polymorphisms with the responsiveness to glucocorticoids in patients with nephrotic syndrome.
The results of these studies on the significance of the genetic polymorphisms are contradictory [ 71 , 82 — 84 , 86 , , , ]. A recent meta-analysis concluded that there is evidence of an association between rs and increased risk of steroid resistance in children with nephrotic syndrome [ ]. Pregnane X receptor PXR gene NR1I2 encodes an intracellular receptor that, upon binding with glucocorticoids or xenobiotic substances, activates a set of genes involved in the metabolism of drugs.
Turolo et al. The hypothesis is that a reduced expression of PXR leads to an underexpression of GRs, which may be the explanation for the development of steroid resistance [ 87 ].
The results of the aforementioned reported papers are generally inconclusive and contradictory. However, some genetic polymorphisms appear to be promising in the prediction of steroid response or steroid-related toxicities in children with nephrotic syndrome. Especially, polymorphisms in the genes encoding for the GR and GR heterocomplex seem to have an association with steroid responsiveness.
Nevertheless, most studies are hampered by small patient cohorts. Therefore, studies in larger cohorts with nephrotic syndrome patients are necessary to draw conclusions about the influence of genetic polymorphisms on the glucocorticoid response.
Furthermore, as mentioned above, pharmacogenetics may also play a role in the intensity and spectrum of side effects. Currently, little is known about the influence of pharmacogenetics on steroid-related toxicities in patients with nephrotic syndrome. However, as previous research in mostly cancer patients has shown a potential role of genetic polymorphisms in the susceptibility on steroid-related toxicities, this area is an important opportunity for future research as well.
Glucocorticoids are essential in the treatment of childhood nephrotic syndrome. Currently, standardized treatment guidelines with high doses of prednisone or prednisolone are proposed worldwide. As current treatment guidelines are largely based on empiric recommendations rather than clinical trials, large variability in the treatment of nephrotic syndrome is present among physicians [ 4 ], especially regarding the treatment of subsequent relapses and the choice of second-line immunosuppressive drugs.
As large-scale clinical trials are lacking, treatment decisions are frequently based on either the preference or common practice of the treating physician or guidelines of the country, rather than the individual characteristics of the patient.
Therefore, effort should be made to first provide international guidelines based on clinical trials to uniformly treat patients with nephrotic syndrome. Subsequently, effort should be made to identify specific markers to individualize treatment, as large inter-individual differences are present in both the clinical course of disease and adverse effects of glucocorticoids in children with nephrotic syndrome. Pharmacogenetics has a promising role in working towards personalized medicine.
Despite the fact that the evidence about the role of pharmacogenetics in children with nephrotic syndrome is limited, we feel that available data do show a potential role for pharmacogenetics in clinical practice to maximize drug efficacy, minimize drug toxicity, and avoid exposure to ineffective drug courses. Nowadays, the evidence to implement these genetic markers in clinical practice is too little and, therefore, clinical implementation of pharmacogenetics in nephrotic syndrome patients is not possible yet.
Therefore, we feel that further research is highly important to identify specific and sensitive markers for steroid resistance in patients without genetic podocyte mutations as well as for patients more at risk for steroid-related toxicities.
As nephrotic syndrome is a rare kidney disease in childhood and large patient cohorts are needed to ultimately implement pharmacogenetics in the clinical work-up, we believe that this research preferably should be conducted in international collaborative studies. Due to decreased protein binding of prednisone and prednisolone in patients with nephrotic syndrome and to more rapid elimination and an increase in volume of distribution, the steady-state unbound concentration.
National Center for Biotechnology Information , U. Pediatric Nephrology Berlin, Germany. Pediatr Nephrol. Published online Mar Anne M. Schijvens , 1 Rob ter Heine , 2 Saskia N.
Schreuder 1. Saskia N. Michiel F. Author information Article notes Copyright and License information Disclaimer. Corresponding author. This article has been cited by other articles in PMC. Abstract Nephrotic syndrome is one of the most common glomerular disorders in childhood. Introduction Nephrotic syndrome is one of the most common glomerular disorders in children and affects 1—7 per , children per year Dutch data 1. Mechanisms of glucocorticoid action Glucocorticoids are potent anti-inflammatory and immunosuppressant drugs.
Genomic mechanisms Fig. Open in a separate window. Non-genomic effects The non-genomic mechanisms of glucocorticoid action remain largely undefined. Pharmacokinetics Pharmacokinetics describes the study of what the body does to a drug.
Prednisone and prednisolone For the treatment of nephrotic syndrome, both prednisone and prednisolone are frequently used glucocorticoids. Absorption Both prednisone and prednisolone are well absorbed after oral administration. Nephrotic syndrome In patients with nephrotic syndrome, a similar bioavailability profile has been described, indicating that the nephrotic state does not influence the absorption of prednisolone and prednisone [ 34 , 37 ] Fig.
Distribution The volume of distribution of prednisolone and prednisone in adults is 0. Nephrotic syndrome Patients with nephrotic syndrome have decreased serum albumin and transcortin levels in the active phase of disease, leading to a decreased protein binding of prednisone and prednisolone [ 37 , 38 ]. Unchanged unbound free concentration in patients with nephrotic syndrome. Nephrotic syndrome For patients with nephrotic syndrome, different dosing regimens have been investigated.
Excretion P-glycoprotein is also located in the liver and kidney, resulting in enhanced excretion of drug substrates into bile and urine, respectively. Nephrotic syndrome In the aforementioned study, children with a variety of diseases e. Summary In patients with nephrotic syndrome, the unbound fraction of prednisolone increases due to saturable protein binding. Pharmacodynamics Pharmacodynamics refers to what the drug does to the body, including the time course and intensity of therapeutic and adverse effects.
Therapeutic effects Clinical efficacy depends on both pharmacokinetic e. Adverse effects Prednisolone and prednisone therapy have been associated with a broad range of toxicities. Nephrotic syndrome As it stands, it is not completely understood how prednisolone achieves remission of nephrotic syndrome.
Isoniazid, salicylates: Increases metabolism of these drugs. Monitor patient closely. Oral anticoagulants: Decreases effects. Use together cautiously. Alfalfa sprouts, astragalus, echinacea, licorice: May interfere with immunosuppressive effect of drug. Discourage use together.
Adverse reactions CNS: euphoria, insomnia, psychotic behavior, pseudotumor cerebri, vertigo, headache, paresthesia, seizures. CV: hypertension, edema, arrhythmias, thrombophlebitis, thromboembolism, heart failure. EENT: cataracts, glaucoma. GI: peptic ulceration, GI irritation, increased appetite, pancreatitis, nausea, vomiting. GU: menstrual irregularities. Metabolic: hypokalemia, hyperglycemia, carbohydrate intolerance. Musculoskeletal: muscle weakness, osteoporosis, growth suppression in children.
Skin: delayed wound healing, acne, various skin eruptions, hirsutism. Please consult with your healthcare provider for more information on indications of use.
When comparing the efficacy of prednisolone and prednisone, it is important to remember that prednisone is the precursor to the active metabolite, prednisolone. Prednisone is metabolized in the liver to prednisolone, and the speed and extent of conversion is dependent upon hepatic function. Researchers compared the conversion of prednisone in patients who showed hepatic impairment to patients with normal liver function.
The plasma concentration of prednisolone was markedly variable in patients with hepatic disease, with some patients showing almost no conversion of the drug. Researchers concluded that there was a great deal of variation of prednisone conversion, and therefore patients with hepatic disease may not be able to dependably convert prednisone to its active metabolite.
Patients with healthy liver function would expect that either prednisolone or prednisone would be effective. Prednisolone is comparable to prednisone on an mg to mg basis. Prednisone is available in higher dose tablets, making the administration of higher doses less complicated. Prednisolone formulations would be preferred in someone with impaired liver function to eliminate the concern over prednisone conversion.
Sign up for prednisone price alerts and find out when the price changes! Prednisolone is a prescription medication that is typically covered by commercial and Medicare plans. Prednisone is also a prescription medication typically covered by both commercial insurance plans and Medicare. It is important to note that for certain disease states, corticosteroids may not be covered under the Medicare drug benefit, but may be covered under Medicare Part B.
Your pharmacist can provide more information on coverage. Prednisone is metabolized to its active metabolite prednisolone by the liver, therefore the potential side effects of each drug closely mirror each other.
Glucocorticoids are known to cause fluid and electrolyte imbalances, which may lead to sodium and fluid retention, high blood pressure, and in some cases, congestive heart failure. Weight gain is a common side effect of corticosteroids. Prolonged use of steroids may slow the growth of children, and for this reason, their use should be limited to as short of a duration as possible to achieve remission of symptoms.
Patients who depend on injectable insulin or other antidiabetic drugs may have to adjust their dose while on steroids. Diabetics may see a rise in their blood sugar even on a very short-term dose of steroids. Non-diabetic patients on long-term steroid therapy may be up to four times more likely to develop diabetes.
The following table is not intended to be a comprehensive list of possible side effects of prednisone and prednisolone. Please consult your pharmacist or physician for a complete list of all side effects. Prednisolone and prednisone are both substrates of the cytochrome P enzyme 3A4. This raises the possibility of drug interactions because numerous other drugs are also metabolized by the P system. Itraconazole and ketoconazole are common antifungal agents. They are also potent inhibitors of CYP 3A4 enzymes.
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