Inhibition Of Drug Metabolism Research Articles

Nephroprotective Effects of Cilastatin in People at Risk of Acute Kidney Injury: A Systematic Review and Meta-analysis

Cilastatin is an inhibitor of drug metabolism in the proximal tubule that demonstrates nephroprotective effects in animals. It has been used in humans in combination with the antibiotic imipenem to block imipenem's renal metabolism. This systematic review and meta-analysis evaluated the nephroprotective effects of cilastatin in humans. Systematic review and meta-analysis of observational (comparative effectiveness) studies or randomized clinical trials (RCTs). People of any age at risk of acute kidney injury (AKI). We systematically searched MEDLINE, Embase, Web of Science, and the Cochrane Controlled Trials registry from database inception to November 2023 for observational studies or RCTs that compared kidney outcomes among groups treated with cilastatin, either alone or as combination imipenem-cilastatin, versus an inactive or active control group not treated with cilastatin. Two reviewers independently evaluated studies for inclusion and risk of bias. Treatment effects were estimated using random-effects models, and heterogeneity was quantified using the I 2 statistic. We identified 10 studies (5 RCTs, n=531patients; 5 observational studies, n=6,321 participants) that met the inclusion criteria, including 4 studies with comparisons to inactive controls and 6 studies with comparisons to alternate antibiotics. Based on pooled results from 7 studies, the risk of AKI was lower with imipenem-cilastatin (risk ratio [RR], 0.52; 95% confidence intervals [CI], 0.40-0.67; I 2=26.5%), with consistent results observed in RCTs (3 RCTs, RR, 0.26; 95% CI, 0.09-0.77; I 2=44.4%) and observational studies (4 studies, RR, 0.54; 95% CI, 0.41-0.72; I 2=44.4%). Based on results from 6 studies, serum creatinine concentration was lower following treatment with imipenem-cilastatin than comparators (weighted mean difference in serum creatinine-0.14 mg/dL (95% CI,-0.21 to-0.07; I 2=0%). The overall certainty of the evidence was low due to heterogeneity of the results, high risk of bias, and indirectness among the identified studies. Clinical and statistical heterogeneity could not be fully explained due to a limited number of studies. Patients treated with imipenem-cilastatin developed AKI less frequently and had lower serum creatinine concentration following treatment than control groups or those who had received comparator antibiotics. Larger clinical trials with less risk of detection bias due to lack of allocation concealment and blinding are needed to establish the efficacy of cilastatin for AKI prevention.

An Retrospective Study of Commonly Prescribed Antiepileptic Drugs and it’s Interaction with Other Drugs which are Already in use Respect to Other Disease

Antiepileptic drugs (AED) are increasingly used in the treatment of some non-epileptic neurological diseases and psychiatric diseases. Most of the available data on the use of these agents in clinical conditions other than epilepsy are from case series, uncontrolled studies, or small randomized clinical trials, and their apparent efficacy requires confirmation in well-designed large phase III trials. Interactions between antiepileptic drugs or between antiepileptic drugs and other drugs can be pharmacokinetic or pharmacodynamic. Pharmacokinetic interactions include changes in absorption, distribution ,or eliminate , while pharmacodynamic interactions include synergism and antagonism at the site ,of action. Most clinically significant antiepileptic drug interactions are due to induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital and primidone are strong inducers of cytochrome P450 and glucuronide enzymes (as well as P-glycoprotein) and may reduce the effectiveness of concomitantly administered drugs such as oral anticoagulants, calcium antagonists, antimicrobial steroids. Mechanism Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate (at doses ≥ 200 mg/day) and perampanel (at doses ≥ 8 mg/day) have weaker inducing properties and less tendency to produce interactions mediated by enzyme induction. In contrast to enzyme induction, enzyme inhibition results in decreased metabolic clearance of the affected drug, which can increase serum concentrations leading to toxic effects. Examples of important interactions mediated by enzyme inhibition include valproic-induced increases in serum concentrations of phenobarbital and lamotrigine. There are also interactions where other drugs induce or inhibit the metabolism of antiepileptic drugs. Examples include an increase in serum carbamazepine concentration due to erythromycin and a decrease in serum lamotrigine concentration due to estrogen-containing contraceptives. Pharmacodynamic interactions between antiepileptic drugs may also be clinically important. These interactions can have potentially beneficial effects, such as the combined therapeutic synergy of valproic acid and lamotrigine, or adverse effects, such as the mutual potentiation of neurotoxicity in patients treated with a combination of sodium channel blocking antiepileptic drugs. AEDs are also used to treat psychiatric conditions, particularly bipolar disorder. To date, the AEDs most commonly used to treat this disorder have been carbamazepine and valproic acid, which have shown manic efficacy and likely long-term mood-stabilizing effects in many bipolar patients, including those who are lithium-intolerant. . The availability of new generation AEDs has expanded treatment options for bipolar disorder. Lamotrigine, oxcarbazepine, gabapentin, and topiramate appear to show promise in the treatment of bipolar disorder, both as monotherapy and in combination with traditional mood stabilizers. In addition, newer AEDs appear to have a more favorable tolerability and drug interaction profile than older compounds, thus improving compliance

Changes in Pharmacodynamic Parameters during Co-administration of 5-FU with Warfarin: A Retrospective Case Series.

Drug-drug interactions (DDIs) between warfarin (WF) and fluoropyrimidines are well known. Co-administration of WF and 5-fluorouracil (5-FU) leads to elevations in prothrombin time international normalised ratio (PT-INR). The inhibition of drug metabolism through suppression of CYP activity is a possible cause of prolonged PT-INR elevations. 5-FU and its metabolites are suspected to inhibit CYPs, but the precise mechanisms of action remain unknown. This study aimed to investigate the possible DDI effects of the co-administration of 5-FU with WF using PT-INR and PT-INR/dose ratio as pharmacodynamic parameters. Retrospective case series data were collected from patients who received parenteral 5-FU chemotherapy from April 2009 to December 2019 at the University of the Ryukyus Hospital. Seven patients who received 5-FU in combination with WF were analysed. There was a significant increase in PT-INR and PT-INR/dose during the co-administration of WF and 5-FU (p = 0.0018 and p = 0.0187, respectively; paired t-test). The findings demonstrated significant DDI between 5-FU and WF evident as elevated PT-INR and PT-INR/dose ratio.

Prescribing Nirmatrelvir/Ritonavir for COVID-19 in Advanced CKD.

Prescribing Nirmatrelvir/Ritonavir for COVID-19 in Advanced CKD.

Niclosamide induces miR-148a to inhibit PXR and sensitize colon cancer stem cells to chemotherapy.

SummaryTumor recurrence is often attributed to cancer stem cells (CSCs). We previously demonstrated that down-regulation of Pregnane X Receptor (PXR) decreases the chemoresistance of CSCs and prevents colorectal cancer recurrence. Currently, no PXR inhibitor is usable in clinic. Here, we identify miR-148a as a targetable element upstream of PXR signaling in CSCs, which when over-expressed decreases PXR expression and impairs tumor relapse after chemotherapy in mouse tumor xenografts. We then develop a fluorescent reporter screen for miR-148a activators and identify the anti-helminthic drug niclosamide as an inducer of miR-148a expression. Consequently, niclosamide decreased PXR expression and CSC numbers in colorectal cancer patient-derived cell lines and synergized with chemotherapeutic agents to prevent CSC chemoresistance and tumor recurrence in vivo. Our study suggests that endogenous miRNA inducers is a viable strategy to down-regulate PXR and illuminates niclosamide as a neoadjuvant repurposing strategy to prevent tumor relapse in colon cancer.

Management of Medication-Induced Psychiatric Disorders.

Management of Medication-Induced Psychiatric Disorders.

Curcuma longa Hepatotoxicity: A Baseless Accusation. Cases Assessed for Causality Using RUCAM Method.

Curcuma longa is a perennial herb that belongs to the Zingiberaceae family. To date, literature includes more than 11.000 scientific articles describing all its beneficial properties. In the last 3 decades various surveys by the U.S. Food and Drug Administration (FDA) concluded that curcumin, the most active ingredient of the drug, is a “generally safe” compound with strong anti-oxidant effects. Curcuma longa was introduced in the daily diet by ayurvedic teachers due to its beneficial effects on health. Nonetheless, recently several reports, from the various global surveillance systems on the safety of plant products, pointed out cases of hepatotoxicity linked to consumption of food supplements containing powdered extract and preparations of Curcuma longa. The latest trend is the use of Curcuma longa as a weight-loss product in combination with piperine, which is used to increase its very low systemic bioavailability. Indeed, only 20 mg piperine, one of the alkaloids found in black pepper (Piper nigrum), assumed at the same time with 2 g curcumin increased 20-fold serum curcumin bioavailability. This combination of natural products is now present in several weight loss supplements containing Curcuma longa. The enhanced drug bioavailability caused by piperine is due to its potent inhibition of drug metabolism, being able to inhibit human P-glycoprotein and CYP3A4, while it interferes with UDP-glucose dehydrogenase and glucuronidation activities in liver. While only few cases of hepatotoxicity, assessed using Roussel Uclaf Causality Assessment Method (RUCAM) method, from prolonged intake of piperine and curcumin have been reported, it would be reasonable to speculate that the suspected toxicity of Curcuma longa could be due to the concomitant presence of piperine itself. Hence, not only there is the need of more basic research to understand the etiopathology of curcumin-related hepatotoxicity and of the combination curcumin-piperine, but human trials will be necessary to settle this dispute.

Elucidation of New Function in Endothelial Cells for Efficient Delivery Strategy of Drug to Tissues

The author has described two new functions of endothelial cells for efficient delivery of drugs to tissues. First, it was indicated that tight junction (TJ)-associated protein, claudin-1, exerts potent paracellular barrier function in cultured mouse lung microvascular endothelial cells (LMECs). This barrier was instantly and reversibly opened by reduction of TJ proteins expression via histamine H1 and H2 receptors. Histamine was biosynthesized by l-histidine decarboxylase from uptaken l-histidine, and biotransformed by type B of monoamine oxidase, suggesting that histamine concentration is controlled in rat brain MECs (BMECs) and LMECs. Moreover, uptake of l-histidine into BMECs and LMECs markedly increased with addition of ZnSO4. Second, it was suggested that drug-metabolizing enzymes such as CYP and flavin-containing monooxygenase exist in vascular endothelial cells exposed to blood and to aerobic conditions. These cells have the same ability to metabolize drugs as hepatocytes, demonstrating that vascular endothelial cells are a metabolic barrier against tissue transfer of drugs. From these results, it was suggested that reversible opening of TJ and selective inhibition of drug metabolism in vascular endothelial cells may be efficient delivery strategies of drugs to tissues. Finally, I hope that this research will lead to development of new drugs and possible re-evaluation of discontinued drugs.

<p>Metabolic profile and structure–activity relationship of resveratrol and its analogs in human bladder cancer cells</p>

Purpose: Resveratrol (RV), a promising anti-cancer candidate, is limited in application for its poor bioavailability. However, the better bioavailability has been found in some RV derivatives. So in this paper, we explore the structure–activity relationship and the metabolic profiles of RV and its analogs (polydatin [PD], oxyresveratrol [ORV], acetylresveratrol [ARV]) in human bladder cancer T24 cells, and then evaluate their active forms and key chemical functional groups which may determine the fate of tumor cells.Methods: Drug sensitivity is evaluated by MTT assay, HE staining and flow cytometry analysis after T24 cells treated with RV, PD, ORV and ARV, respectively. Then the drug metabolites, in alive and dead T24 cells, also in T24 cell supernatant and lysates, are qualitatively and quantitatively analyzed by high-performance liquid chromatography, liquid chromatography coupled with tandem mass spectrum and high-resolution mass spectrometry technologies, respectively.Results: RV, ORV and ARV inhibit bladder cancer cells growth in a dose- and time-dependent manner, and exert the anti-tumor potency to T24 cells in order of ORV>ARV>RV>PD. Meanwhile, similar metabolic profiles of the above compounds are found not only in cell supernatant and lysate, but also in dead and alive T24 cells after drug treatment, and the main metabolites of RV, ORV and PD are their prototypes, but ARV is mainly metabolized to RV.Conclusion: The inhibitory potencies to T24 cells in the order of ORV>ARV>RV>PD are related to the structure and metabolism of RV and its analogs. Meanwhile, the number and position of free phenolic hydroxyl groups play a prominent role in antitumor activities. Therefore, protecting phenolic hydroxyl groups, and inhibiting drug metabolism to keep phenolic hydroxyl groups free would be the promising strategies to ensure the bioactivity of RV and its analogs, and thus to improve RV’s bioactivity and promote RV clinical translation.

Abnormal QTc syndrome in HIV-infected patients: a systematic review of prevalence and risk factors.

The purpose of this review is to critically analyse data regarding the prevalence and risk factors for developing a prolonged QTc interval and subsequent sudden cardiac death (SCD) in persons living with HIV (PLWH). A systematic literature search using PubMed and Google Scholar databases was performed using the following search terms: 'HIV and prolonged QTc' and 'managing HIV-patients with prolonged QTc'. References within articles of interest were also evaluated. PLWH are at an increased risk of having a prolonged QTc interval. Some risk factors for this include the virus itself, concomitant medications, comorbid conditions, addictions and electrolyte disturbances. PLWH who have an increased HIV RNA viral load or decreased CD4+ T-cell count are at further risk for progressing to sudden cardiac death (SCD). Many medications commonly prescribed in the PLWH population, such as antiretrovirals and antimicrobials used in opportunistic infection prophylaxis, have also been shown to promote QTc prolongation through inhibition of human ether-a-go-go potassium channels or through drug metabolism inhibition of other QTc prolonging drugs. Due to the high number of risk factors associated with QTc prolongation, clinicians should incorporate baseline and routine ECG monitoring for PLWH to potentially lower the increased risk of SCD in PLWH.

Role of Piperine as an Effective Bioenhancer in Drug Absorption

Bioenhancers can be defined as chemical entities, which when mixed with drugs promote and augment their bioavailability without showing any synergistic effect with the drug. The factors like toxicity, cost, poor bioavailability and long term administration of drugs give rise to the need of bioenhancers which help overcome most of these problems. Piper species produce a pungent alkaloid named Piperine or 1-peperoyl piperidine. Piperine increases permeability at the site of absorption by modulating lipid environment and membrane dynamics. Piperine has a molecular structure that is suitable for enzyme inhibition. It augments the bioavailability of several drugs like carbamazepine, curcumin, ciprofloxacin, ampicillin, metronidazole, oxytetracycline and many others by inhibiting various metabolizing enzymes. Thus piperine, being an efficacious inhibitor of drug metabolism is a powerful enhancer of absorption. The following review explores the mechanism, metabolism inhibition, influence of structural changes on activity, and drugs bioenhanced by piperine. It provides an insight on the application of piperine as an effective bioenhancer and the superiority of a bioenhanced drug formulation over the one without a bioenhancer. This concept which is found to be beneficial, has its roots in Ayurveda-the traditional Indian system of medicine and has been applied to various drugs. It presents a fine instance of the advantage of amalgamating a traditional system with contemporary medicine.

Piperine Decreases Binding of Drugs to Human Plasma and Increases Uptake by Brain Microvascular Endothelial Cells.

We previously reported that piperine, an active alkaloidal principal of black and long peppers, enhances drug bioavailability by inhibiting drug metabolism. Another mechanism influencing drug availability/uptake is its free fraction. Since piperine is highly lipophilic, we hypothesize that it could also interact with drugs through binding displacement and influence their bioavailability. Accordingly, using equilibrium dialysis, we investigated whether piperine alters the binding of model drug ligands, that is flunitrazepam, diazepam, warfarin, salicylic acid, propranolol, lidocaine, and disopyramide to human plasma (n=4). Since alterations in binding influence drug disposition, we also studied the effects of piperine on the uptake of plasma bound 3 H-propranolol and 14 C-warfarin by cultured bovine brain microvascular endothelial cells (BMECs). Piperine (1-1000μM) increased the free fraction (fu) of both albumin and alpha-acid glycoprotein bound drugs in a concentration-dependent manner (p<0.01). Moreover, piperine (10μM) increased the uptake of 3 H-propranolol and 14 C-warfarin by BMECs (p<0.01). In conclusion, our findings provide the first evidence that piperine displaces plasma bound drugs from both albumin and alpha-acid glycoprotein and facilitates drug uptake across biological membranes (e.g. BMEC). Moreover, it is feasible that piperine may similarly facilitate the transport of drugs into tissues, in vivo, and alter both pharmacokinetics and pharmacodynamics of administered drugs. Copyright © 2017 John Wiley & Sons, Ltd.

Quantitative prediction of the extent of drug–drug interaction using a physiologically based pharmacokinetic model that includes inhibition of drug metabolism determined in cryopreserved hepatocytes

1. A physiologically based pharmacokinetic (PBPK) model that includes inhibition constant evaluated in cryopreserved hepatocytes was used to predict drug–drug interactions (DDIs) between orally administered nifedipine, a CYP substrate, and fluconazole or ketoconazole, CYP inhibitors, in rats.2. The Kp,uu, ratio of unbound inhibitor concentration in liver ([I]liver,u) to that in plasma ([I]sys,u), of fluconazole and ketoconazole was 1.0 and 13.0, indicating that ketoconazole accumulates in liver. The ratios of inhibition constants in rat liver microsomes (Ki,mic,u) to that in rat cryopreserved hepatocytes (Ki,hep,u) for fluconazole and ketoconazole were 1.5 and 25.5, which were similar to the Kp,uu and suggested that cryopreserved hepatocytes could mimic the hepatic accumulation of inhibitors.3. The increases in AUC of nifedipine predicted by the minimal PBPK model using [I]liver,u/Ki,mic,u and [I]sys,u/Ki,hep,u were within 1.5-fold of the observed values for both inhibitors, whereas the model using [I]sys,u/Ki,mic,u underestimated the AUC increase caused by ketoconazole 21-fold.4. These results indicated that hepatic accumulation factor of an inhibitor is required for a precise DDI projection and that cryopreserved hepatocytes would be useful to obtain the Ki including hepatic accumulation factor. It was demonstrated that PBPK model using Ki,hep,u could be a valuable approach for quantitative DDI projection.

PIPERINE: A NATURAL BIOENHANCER

Herbal sources have been explored recently at very high frequency owing to their lower risk benefit ratio as compared to the modern allopathic medicine systems. Herbal bioenhancer is an agent of herbal origin or any phytomolecule, which is capable of enhancing bioavailability and bioefficacy of a particular drug or nutrient with which it is combined, without any typical pharmacological activity of its own at the dose used. The active compound of both Long pepper ( Piper longum ) and Black pepper ( Piper nigrum ) is piperine (1-piperoyl piperidine), which is responsible for bioenhancing effect. Piperine enhances absorption from gastrointestinal tract by various mechanisms and reduces gut metabolism of drugs. Piperine modulates membrane dynamics and lipid environment and increases permeability at site of absorption. Thus, piperine acts as absorption enhancer and is a potent inhibitor of drug metabolism as it inhibits various metabolizing enzymes like human p-glycoproteins, CYP3A4, UDP-glucose dehydrogenase (UDP-GDH), aryl hydrocarbon hydroxylase (AAH) and UDP-glucuronyl transferase. The current review also describes the mechanism of action of piperine and bioavailability action of piperine on drugs and nutrients.

Piperine and Its Various Physicochemical and Biological Aspects: A Review

Piper nigrumL. is examined as the king of species worldwide by virtue of its principle piperine. In Ayurveda, since from the ancient times, it is known as “Yogvahi”. It is one of the important alkaloids of Pepper fruits (Family Piperaceae) and has been found to have numerous medicinal properties such as antioxidant, antiplatelet, anti-inflammatory, antihypertensive, hepatoprotective, antithyroid, antitumor, antiasthmatic activity and also have significant role as fertility enhancer. The present review discusses the biosynthetic pathway, extraction process, chemistry and various analytical methods of piperine. It also describes the structural modification of piperine and its various effects on biological system. The utility of piperine as a bioenhancer for certain antibacterial- antibiotics and a potent inhibitor of drug metabolism are also discussed. Thus, review provides knowledgeable erudition on the piperine which paves way for further work.

Effects of Miconazole Oral Gel on Blood Concentrations of Tacrolimus and Cyclosporine: A Retrospective Observational Study.

Although azole antifungal agents have been shown to affect the pharmacokinetics of calcineurin inhibitors such as tacrolimus (TAC) and cyclosporine (CyA) by inhibiting drug metabolism, there are few clinical reports on drug interactions between miconazole (MCZ) oral gel and calcineurin inhibitors. In this study, the effects of MCZ oral gel on the blood concentrations of TAC and CyA were investigated. In this retrospective study, 18 patients concomitantly administered MCZ oral gel and TAC (9 for dermatomyositis, 3 for myasthenia gravis, 2 for systemic lupus erythematosus, 2 for rheumatoid arthritis, 1 for polymyositis, 1 for prevention of graft-versus-host disease after bone marrow transplantation), and 15 patients concomitantly administered MCZ oral gel and CyA (11 for interstitial pneumonia, 2 for pemphigus, 1 for eosinophilic granulomatosis with polyangiitis, 1 for systemic lupus erythematosus) were evaluated. The dose-adjusted blood concentrations of TAC or CyA were compared before and after the initiation of MCZ oral gel. The trough blood concentration/dose (C/D) ratios of TAC and CyA increased significantly with the administration of MCZ oral gel. The median C/D ratios of TAC and CyA increased by 108% (range: -44% to 216%) and 44% (range: -34% to 195%), respectively. These results suggest that MCZ oral gel affects the pharmacokinetics of TAC and CyA. Detailed monitoring of the blood concentrations of these drugs, followed by dose adjustments, is needed for each patient because of the difficulties associated with accurately predicting the degree of the effects of MCZ oral gel.

No Increased Risk of Ketoconazole Toxicity in Drug-Drug Interaction Studies.

In July 2013 the U.S. Food and Drug Administration (FDA) released a safety announcement regarding the use of ketoconazole and its adverse drug reactions. The FDA report advised against the use ketoconazole tablets as a first-line treatment for any fungal infections because of the risk of potentially serious drug-drug interactions and liver and adrenal gland complications. The European Medicines Agency (EMA) also proposed to limit the use of oral ketoconazole in fungal infections because of the same risk of harmful effects and interactions. In addition, the FDA also advised against the use of oral ketoconazole in drug interaction studies, in which it has been extensively used as an index inhibitor of drug metabolism. The aim of this investigation was to evaluate the risks of ketoconazole-induced hepatotoxicity described by the FDA and EMA in published drug interaction studies with ketoconazole and compare these data with the toxicity reported for ketoconazole when used as antifungal treatment. In the drug interaction studies (2355 participants; healthy volunteers and patients; median treatment duration, 6 days), only 40 participants were reported to have increased liver transaminase activity (1.7%), and no deaths were reported or associated with ketoconazole. In studies investigating ketoconazole treatment, patients were treated for 276 days (median), and 5.6% of patients had elevated liver enzyme activity. Because of the short treatment period in drug interaction studies the risk of drug-induced hepatic injury is considered very low. As such, we recommend that ketoconazole remain a safe CYP3A index inhibitor for use in drug interaction studies with healthy volunteers.

Esterase profiles of organophosphorus compounds in vitro predict their behavior in vivo

We studied 4 serine esterases (EOHs) that are associated with the following consequences from their inhibition by organophosphorus compounds (OPCs): acetylcholinesterase (AChE: acute neurotoxicity; cognition enhancement), butyrylcholinesterase (BChE: inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors; cognition enhancement), carboxylesterase (CaE; inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors), and neuropathy target esterase (NTE: delayed neurotoxicity, OPIDN). The relative degree of inhibition of these EOHs constitutes the “esterase profile” of an OPC, which we hypothesize can serve as a predictor of its overall physiological effects. To test this hypothesis, we selected 3 OPCs known from previous work on reference enzymes to span a wide range of esterase profiles, neuropathic potential, and acute cholinergic toxicity. For each compound, we determined in vitro IC50 and in vivo ED50 values for inhibition of AChE, BChE, CaE, and NTE in mouse brain and blood. The results showed good correlations between in vitro and in vivo measures of potency and selectivity except for brain CaE, a tissue-specific isoform of the enzyme that was less sensitive to the test compounds than expected. Thus, this synthesis of new and previously published results indicates that the concept of the esterase profile of OPCs is useful for the prediction of therapeutic and toxic effects in vivo.

Seizures and cancer: drug interactions of anticonvulsants with chemotherapeutic agents, tyrosine kinase inhibitors and glucocorticoids.

Patients with cancer commonly experience seizures. Combined therapy with anticonvulsant drugs (AEDs) and chemotherapeutic drugs or tyrosine kinase inhibitors carries inherent risks on drug-drug interactions (DDIs). In this review, pharmacokinetic studies of AEDs with chemotherapeutic drugs, tyrosine kinase inhibitors, and glucocorticoids are discussed, including data on maximum tolerated dose, drug clearance, elimination half-life, and organ exposure. Enzyme-inducing AEDs (EIAEDs) cause about a 2-fold to 3-fold faster clearance of concurrent chemotherapeutic drugs metabolized along the same pathway, including cyclophosphamide, irinotecan, paclitaxel, and teniposide, and up to 4-fold faster clearance with the tyrosine kinase inhibitors crizotinib, dasatinib, imatinib, and lapatinib. The use of tyrosine kinase inhibitors, particularly imatinib and crizotinib, may lead to enzyme inhibition of concurrent therapy. Many of the newer generation AEDs do not induce or inhibit drug metabolism, but they can alter enzyme activity by other drugs including AEDs, chemotherapeutics and tyrosine kinase inhibitors. Glucocorticoids can both induce and undergo metabolic change. Quantitative data on changes in drug metabolism help to apply the appropriate dose regimens. Because the large individual variability in metabolic activity increases the risks for undertreatment and/or toxicity, we advocate routine plasma drug monitoring. There are insufficient data available on the effects of tyrosine kinase inhibitors on AED metabolism.

Identification and Mechanistic Investigation of Drug-Drug Interactions Associated With Myopathy: A Translational Approach.

Myopathy is a group of muscle diseases that can be induced or exacerbated by drug–drug interactions (DDIs). We sought to identify clinically important myopathic DDIs and elucidate their underlying mechanisms. Five DDIs were found to increase the risk of myopathy based on analysis of observational data from the Indiana Network of Patient Care. Loratadine interacted with simvastatin (relative risk 95% confidence interval [CI] = [1.39, 2.06]), alprazolam (1.50, 2.31), ropinirole (2.06, 5.00), and omeprazole (1.15, 1.38). Promethazine interacted with tegaserod (1.94, 4.64). In vitro investigation showed that these DDIs were unlikely to result from inhibition of drug metabolism by CYP450 enzymes or from inhibition of hepatic uptake via the membrane transporter OATP1B1/1B3. However, we did observe in vitro synergistic myotoxicity of simvastatin and desloratadine, suggesting a role in loratadine–simvastatin interaction. This interaction was epidemiologically confirmed (odds ratio 95% CI = [2.02, 3.65]) using the data from the US Food and Drug Administration Adverse Event Reporting System.