Life-threatening Drug Interactions Research Articles

Pharmacokinetics of Dasatinib in Rats: a Potential Food-Drug Interaction with Naringenin.

The novel tyrosine kinase inhibitor (TKI) dasatinib, a multitarget inhibitor of Bcr-Abl and Src family kinases, has been licensed for the treatment of Ph+ acute lymphoblastic leukemia and chronic myeloid leukemia. Many citrus-based foods include the flavonoid naringenin, which is commonly available. Dasatinib is a Cyp3a4, P-gp, and Bcrp1 substrate, which makes it sensitive to potential food-drug interactions. The concurrent use of naringenin may change the pharmacokinetics of dasatinib, which could result in adverse effects and toxicity. The present investigation examined the impact of naringenin on the pharmacokinetics interactions of DAS and proposes a possible interaction mechanism in Wistar rats. Rats were provided with a single oral dose of dasatinib (25mg/kg) with or without naringenin pretreatment (150mg/kg p.o. daily for 7days, n = 6 in each group). Dasatinib was quantified in plasma by UHPLC MS/MS assay. Noncompartmental analysis was used to compute the pharmacokinetic parameters, and immunoblot was used to assess the protein expression in the hepatic and intestinal tissues. Following 7 days of naringenin pretreatment, the plasma mean concentration of dasatinib was enhanced compared with without pretreatment. In rats that were pretreated with naringenin, the pharmacokinetics of the orally administered dasatinib (25mg/kg) was shown to be significantly different from that of dasatinib given without pretreatment (p < 0.05). There was a significant enhancement in pharmacokinetic parameterselimination half-life (T1/2),time to maximum concentration ( Tmax), maximum concentration )Cmax), area under the concentration-time curve (AUC0-t),area under the moment curve (AUMC0-∞), and mean residence time (MRT) by 28.41%, 50%, 103.54%, 72.64%, 115.08%, and 15.19%, respectively (p < 0.05) and suppression in elimination rate constant (Kel), volume of distribution (Vd), and clearance (CL) by 21.09%, 31.13%, and 46.25%, respectively, in comparison with dasatinib alone group (p < 0.05). The enhancement in dasatinib bioavailability and systemic exposure resulted from the significant inhibition of Cyp3a2, Mdr1/P-gp, and Bcrp1 expression and suppression of the dasatinib hepatic and intestinal metabolism, which enhanced the rate of dasatinib absorption and decreased its elimination. Concurrent use of naringenin-containing supplements, herbs, or foods with dasatinib may cause serious and potentially life-threatening drug interactions. Further studies are necessary to determine the clinical significance of these findings.

Herb-drug interaction: Effect of sinapic acid on the pharmacokinetics of dasatinib in rats

Dasatinib (DAS) is a narrow therapeutic index drug and novel oral multitarget inhibitor of tyrosine kinase and approved for the first-line therapy for chronic myelogenous leukemia (CML) and Philadelphia chromosome (Ph + ) acute lymphoblastic leukemia (ALL). DAS, a known potent substrate of cytochrome (CYP) 3A, P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) and is subject to auto-induction. The dietary supplementation of sinapic acid (SA) or concomitant use of SA containing herbs/foods may alter the pharmacokinetics as well as pharmacodynamics of DAS, that may probably lead to potential interactions. Protein expression in rat hepatic and intestinal tissues, as well as the in vivo pharmacokinetics of DAS and the roles of CYP3 A2 and drug transporters Pgp-MDR1 and BCPR/ABCG2, suggested a likely interaction mechanism. The single dose of DAS (25 mg/kg) was given orally to rats with or without SA pretreatment (20 mg/kg p.o. per day for 7 days, n = 6). The plasma concentration of DAS was estimated by using Ultra-High-Performance Liquid Chromatography Mass spectrometry (UHPLC-MS/MS). The in vivo pharmacokinetics and protein expression study demonstrate that SA pretreatment has potential to alter the DAS pharmacokinetics. The increase in Cmax, AUC and AUMC proposes increase in bioavailability and rate of absorption via modulation of CYP3 A2, PgP-MDR1 and BCPR/ABCG2 protein expression. Thus, the concomitant use of SA alone or with DAS may cause serious life-threatening drug interactions.

Effects of Apigenin on Pharmacokinetics of Dasatinib and Probable Interaction Mechanism.

Dasatinib (DAS), a narrow-therapeutic index drug, Bcr-Abl, and Src family kinases multitarget inhibitor have been approved for chronic myelogenous leukemia (CML) and Ph-positive acute lymphocytic leukemia (Ph+ ALL). Apigenin (APG) has a long history of human usage in food, herbs, health supplements, and traditional medicine, and it poses low risk of damage. The concomitant use of APG containing herbs/foods and traditional medicine may alter the pharmacokinetics of DAS, that probably lead to possible herb-drug interactions. The pharmacokinetic interaction of APG pretreatment with DAS in rat plasma following single and co-oral dosing was successfully deliberated using the UPLC-MS/MS method. The in vivo pharmacokinetics and protein expression of CYP3A2, Pgp-MDR1, and BCPR/ABCG2 demonstrate that APG pretreatment has potential to drastically changed the DAS pharmacokinetics where escalation in the Cmax, AUC(0-t), AUMC(0-inf_obs), T1/2, Tmax, and MRT and reduction in Kel, Vd, and Cl significantly in rats pretreated with APG 40 mg/kg, thus escalating systemic bioavailability and increasing the rate of absorption via modulation of CYP3A2, Pgp-MDR1, and BCPR/ABCG2 protein expression. Therefore, the concomitant consumption of APG containing food or traditional herb with DAS may cause serious life-threatening drug interactions and more systematic clinical study on herb-drug interactions is required, as well as adequate regulation in herbal safety and efficacy.

Risk Assessment of "Other Substances" – L- tryptophan

Risk Assessment of "Other Substances" – L- tryptophan

TWO HITS FOR LACTIC ACIDOSIS: A STUDY IN DRUG-DRUG INTERACTION

SESSION TITLE: Wednesday Fellows Case Report Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Tumors with high mitotic activity undergo oxidative phosphorylation for ATP synthesis. In acute myelogenous leukemia (AML) new therapies that target energy metabolism and mitochondrial protein synthesis are being studied. When these new drugs are combined with medications that also effect mitochondrial activity serious complications may occur. Particularly when side-effects from new investigation therapies are not widely known, nor available to automated electronic medical record (EMR) drug interaction checks. We present a case of life-threatening lactic acidosis due to the use of a STAT3 (signal transduction activator of transcription) inhibitor - a drug currently in clinical trials -- in a patient also receiving linezolid, in whom the risk of a life-threatening drug interaction and toxicity was not fully appreciated. CASE PRESENTATION: A 61 year-old man with a history of refractory AML in a clinical trial with a STAT 3 inhibitor presented with sepsis, but despite appropriate antibiotics his clinical status declined requiring mechanical ventilation. Lab studies showed a rapidly worsening lactic acidosis (3.9 to 18 mmol/L) over a few hours. Later it was discovered that he had completed a prolonged course of linezolid for vancomycin-resistant enterococcus bacteremia the day prior to admission. Though inputted in the medical record as an investigation study drug, the drug-drug interaction with linezolid was not registered by the EMR. Plasmapheresis and dialysis were used to remove residual linezolid and the study drug. Subsequently his lactate decreased to 2.4 and he was extubated. However, given the lack of treatment options for refractory AML the family decided to pursue comfort measures. DISCUSSION: STAT3 is a member of the STAT family of proteins involved in intracellular and extracellular signals to the nucleus, controlling gene expression. STAT3 is involved in AML cells, antiapoptosis genes, cell cycle regulators and promotes OXPHOS (oxidative phosphorylation). A major concern for the use of OXPHOS inhibitors is lactic acidosis. Similarly, linezolid decreases mitochondrial respiratory chain enzyme activity, hence disrupting cellular energy production. In our patient, it is likely that the use of two OXPHOS inhibitors resulted in severe mitochondrial toxicity and lactic acidosis. With new medications being developed that inhibit mitochondrial oxidative phosphorylation, intensive care units may see patients who are suffering from their side effects. CONCLUSIONS: This case highlights the importance of reviewing mechanisms and adverse effects of study drugs. Our case also reminds us that study drugs may not be included in the EMR or not flagged by computerized drug interaction alerts. We believe the use of STAT3 inhibitor and other new OXPHOS inhibitors warrant careful monitoring, particularly when used simultaneously with other medications that increase the risk of mitochondrial toxicity. Reference #1: Redell MS, Ruiz MJ, Alonzo TA, Gerbing RB, Tweardy DJ. Stat3 signaling in acute myeloid leukemia: ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor. Blood. 2011;117(21):5701-9. DISCLOSURES: No relevant relationships by Alan Gandler, source=Web Response No relevant relationships by Alexys Monoson, source=Web Response No relevant relationships by David Oxman, source=Web Response No relevant relationships by MRINALINI VENKATA SUBRAMANI, source=Web Response

A road to bring Brij52 back to attention: Shear stress sensitive Brij52 niosomal carriers for targeted drug delivery to obstructed blood vessels

Thrombosis is a shared perpetrating event in the pathophysiology of several cardiovascular disorders such as ischemic stroke, venous thromboembolism, atherosclerosis, and myocardial infarction. Despite holding a wide range of ammunition in our arsenal to ameliorate such conditions, we are still facing with many stumbling blocks in the satisfactory pharmacotherapy of cardiovascular diseases among which the risk of hemorrhage and life threatening drug interactions can be highlighted. Our hypothesis focuses on mimicking the nature of platelet activation, to design a novel targeted delivery system based on the alterations of a physical parameter, the hemodynamic shear stress, to aim at the offending thrombi in an attempt to offer a noninvasive, rapid, and monitoring-free method that not only can prolong the circulation time of the cargo, but also deliver it locally and reduce both the undesirable adverse effects and drug interactions. Brij52 is our chosen candidate due to its unique non-spherical morphology after forming a niosomal vesicle. We surmised that thanks to its non-spherical shape, diverse shear rates may generate different shear stresses to its equators and axes which might result in the breakdown or at least distortion of niosomal structure under elevated shear stress. The vesicles have to be synthesized in the size of platelets or in the nano-sized scale. In order to prolong the time vesicles are circulating in the blood, PEGylation may help and to make such carriers highly selective to be only activated during pathophysiological clot formation, attachment of domain A1 von Willebrand factor can be of benefit to lead this proposed delivery system to the site of thrombus formation where shear rate exceeds those of 1000 s−1. There is now an emerging fast growing universal research on shear activated carriers, and the present theory is an endeavor to reach a successful treatment strategy to combat cardiovascular diseases based on the hypothesis that a non-spherical nano-carrier such as Brij 52 niosomal vesicle can be of paramount benefit to deliver current antithrombotic agents in a targeted and controlled manner in the presence of elevated shear stress of the obstructed blood vessels. With more radical advanced drug delivery systems being developed and new strategies being pursued, there will be more options in our arsenal to represent a promising avenue for achieving preventive, well-tolerated, and intelligent drug carriers to circumvent the drawbacks of antithrombotic pharmacotherapy.

Catastrophic Drug-Drug Interactions in Psychopharmacology

Drug interactions may reflect pharmacokinetic processes, pharmacodynamic processes, or both. Some interactions are classified as idiosyncratic, as their mechanisms are not yet understood. Drug interactions involving psychotropic medications are ubiquitous; they typically result in changes in drug levels and/or drug effects. Fortunately, most drug interactions in psychiatry do not result in serious harm. Some drug interactions, however, are potentially catastrophic. The focus of this review is on the principal mechanisms of drug interactions and on potentially serious and life-threatening adverse consequences (eg, serotonin syndrome, hypertensive crises, arrhythmias, anticholinergic toxicity, seizures, dermatologic emergencies, bleeding, respiratory depression) of drug interactions in psychiatry. Patients with refractory psychiatric disorders, as well as medical comorbidity, often require treatment with complex drug regimens. The risk of catastrophic drug interactions involving psychotropic medications may be minimized by knowledge of the mechanisms of drug interactions and by familiarity with the rare, yet potentially life-threatening drug interactions that involve psychotropic medications. [ Psychiatr Ann . 2016;46(8):439–447.]

Serotonin Syndrome after Initiation of Pregabalin on a Stable Regimen of Antidepressant Medication

Aims: Serotonin syndrome is a potentially life-threatening drug interaction caused by excess serotonin concentration in the central nervous system and/or peripheral nervous system leading to cognitive, autonomic and somatic effects ranging from barely perceptible to fatal. A number of drugs and drug interactions cause serotonin syndrome, however, the exact mechanisms often remain elusive. Presentation of Case: In the following case, serotonin syndrome was caused by the addition of pregabalin in a patient with recurrent major depressive disorder and concurrent medication with paroxetine and trazodone. Discussion: This case illustrates the risk of polypsychopharmacology leading to an increased vulnerability towards serotonin syndrome. Conclusion: Pregabalin with its serotonergic action has a liability to cause serotonin syndrome. This should be especially kept in mind in patients with polypsychopharmacology.

The Rate of Physicochemical Incompatibilities, Administration Errors. Factors Correlating with Nurses' Errors.

Medication errors are commonly encountered in hospital setting. Intravenous medications pose particular risks because of their greater complexity and the multiple steps required in their preparation, administration and monitoring. We aimed to determine the rate of errors during the preparation and administration phase of intravenous medications and the correlation of these errors with the demographics of nurses involved in the process. One hundred patients who were receiving IV medications were monitored by a trained pharmacist. The researcher accompanied the nurses during the preparation and administration process of IV medications. Collected data were compared with the acceptable guidelines. A checklist was filled for each IV medication. Demographic data of the nurses were collected as well. A total of 454 IV medications were recorded. Inappropriate administration rate constituted a large proportion of errors in our study (35.3%). No significant or life threatening drug interaction was recorded during the study. Evaluating the impact of the nurses' demographic characteristics on the incidence of medication errors showed that there is a direct correlation between nurses' employment status and the rate of medication errors, while other characteristics did not show a significant impact on the rate of administration errors. Administration errors were significantly higher in temporary 1-year contract group than other groups (p-value < 0.0001). Study results show that there should be more vigilance on administration rate of IV medications to prevent negative consequences especially by pharmacists. Optimizing the working conditions of nurses may play a crucial role.

Urine Specimen Detection of Concurrent Nonprescribed Medicinal and Illicit Drug Use in Patients Prescribed Buprenorphine

Patients being treated with buprenorphine usually have a history of opioid dependence and may be predisposed to misuse of drugs. Concurrent drug misuse increases the risk of life-threatening drug interactions. This retrospective data analysis observed which nonprescribed and illicit drugs were most commonly detected in the urine of patients from pain management clinics taking buprenorphine with or without a prescription. GC, LC/MS and LC-MS-MS were used to quantify 20,929 urine specimens. The most prevalent illicit drug used in both the groups (prescribed and nonprescribed buprenorphine) was marijuana, followed by cocaine. The most prevalent nonprescribed medications abused by both the groups were benzodiazepines, followed by oxycodone and hydrocodone. The overall prevalence of illicit and nonprescribed drug use was significantly higher in subjects who used buprenorphine without a prescription versus prescribed use. Of the concurrent use of marijuana and cocaine with buprenorphine, cocaine is most concerning since it decreases exposure to buprenorphine (lower area under the concentration-time curve and maximum concentration). The concurrent use of nonprescribed benzodiazepines with buprenorphine can cause excess sedation leading to respiratory depression and even death. These findings highlight the importance of educating patients about these potential toxicities. Furthermore, pain providers should consider expanding the spectrum of drugs that they monitor in patients under treatment.

Diabetic ketoacidosis: an overlooked child killer in sub‐Saharan Africa?

The true incidence of diabetic ketoacidosis (DKA) in sub-Saharan Africa is unknown but unlike in the Western countries, DKA is also uniquely frequent among type 2 diabetes patients of African origin. Increased hyperglycaemia and hepatic ketogenesis lead to osmotic diuresis, dehydration and tissue hypoxia. Acute complications of DKA include cerebral oedema, which may be compounded by malnutrition, parasitic and microbial infections with rampant tuberculosis and HIV. Overlapping symptoms of these conditions and misdiagnosis of DKA contribute to increased morbidity and mortality. Inability of the patients to afford insulin treatment leads to poor glycemic control as some patients seek alternative treatment from traditional healers or use herbal remedies further complicating the disease process. Standard treatment guidelines for DKA currently used may not be ideal as they are adapted from those of the developed world. Children presenting with suspected DKA should be screened for comorbidities which may complicate fluid and electrolyte replacement therapy protocol. Patient rehabilitation should take into account concurrent treatment for infectious conditions to avoid possible life-threatening drug interactions. We recommend that health systems in sub-Saharan Africa leverage the Expanded Immunization Programme or TB/HIV/AIDS programmes, which are fairly well entrenched to support diabetes services.

Economic Impact of Inappropriate Benzodiazepine Prescribing and Related Drug Interactions Among Elderly Persons

The purpose of this study was to describe, from a health care system perspective, potentially inappropriate benzodiazepine prescribing among elderly persons in a publicly funded health system in Canada as well as health service use and costs associated with such prescriptions and the related drug interactions. The sample (N=2,320) was representative of Quebec's community-dwelling elderly population (≥ 65 years) and consisted of respondents to the 2006 ESA survey (Enquête sur la Santé des Aînés, or Survey on the Health of the Elderly). The definition of potentially inappropriate benzodiazepine prescription was based on Beers criteria and on the potential for benzodiazepine-related drug interactions. Using a retrospective design, logistic regressions tested the association between inappropriate prescribing and health service use incurred over 12 months. The cost analysis used a generalized linear model with a gamma distribution. Thirty-two percent (N=744) had received a benzodiazepine prescription, and 44% of this group received at least one potentially inappropriate prescription. Participants susceptible to benzodiazepine-related drug interactions, unlike those with inappropriate prescriptions according to Beers criteria, had a greater risk of hospitalizations and of emergency department and outpatient visits and higher health care costs ($3,076 higher per year, p<.001) than those with appropriate prescriptions. Use of administrative and survey data permitted control for several factors, and a significant association between benzodiazepine-related drug interactions and health care costs among elderly persons was found. Research should further examine this association and evaluate the potential of shared medical electronic databases to decrease life-threatening drug interactions affecting this population.

Clinically significant psychotropic drug-drug interactions in the primary care setting.

In recent years, the growing numbers of patients seeking care for a wide range of psychiatric illnesses in the primary care setting has resulted in an increase in the number of psychotropic medications prescribed. Along with the increased utilization of psychotropic medications, considerable variability is noted in the prescribing patterns of primary care providers and psychiatrists. Because psychiatric patients also suffer from a number of additional medical comorbidities, the increased utilization of psychotropic medications presents an elevated risk of clinically significant drug interactions in these patients. While life-threatening drug interactions are rare, clinically significant drug interactions impacting drug response or appearance of serious adverse drug reactions have been documented and can impact long-term outcomes. Additionally, the impact of genetic variability on the psychotropic drug's pharmacodynamics and/or pharmacokinetics may further complicate drug therapy. Increased awareness of clinically relevant psychotropic drug interactions can aid clinicians to achieve optimal therapeutic outcomes in patients in the primary care setting.

Adverse interactions between antifungal azoles and vincristine: review and analysis of cases

Triazole and imidazole antifungal agents inhibit metabolism of vincristine, leading to excess vinca alkaloid exposure and severe neurotoxicity. Recent reports of debilitating interactions between vincristine and itraconazole, as well as posaconazole, voriconazole and ketoconazole underscore the need to improve medical awareness of this adverse combination. We, therefore, undertook a comprehensive analysis of reports of adverse drug interactions (ADIs) with the combination of vincristine and azole antifungal agents, established a new classification, and provided a detailed summary of these toxicities. In patients who had sufficient data for analysis, 47 individuals were identified who had an ADI with the combination of vincristine and antifungal azoles. Median age was 8 years (1.3-68 years) with 33(70%) having a diagnosis of acute lymphoblastic leukaemia. Median time to ADI with vincristine was 9.5 days with itraconazole, 13.5 days posaconazole and 30 days voriconazole. The median number of vincristine doses preceding the ADI was 2 doses with itraconazole, 3 doses posaconazole and 2 doses voriconazole. The most common severe ADIs included gastrointestinal toxicity, peripheral neuropathy, hyponatremia/SIADH, autonomic neuropathy and seizures. Recovery from these ADIs occurred in 80.6% of patients. We recommend using alternative antifungal agents if possible in patients receiving vincristine to avoid this serious and potentially life-threatening drug interaction.

Risk of severe serotonin toxicity following co-administration of methylene blue and serotonin reuptake inhibitors: an update on a case report of post-operative delirium

In a previous case report, published in this journal, we described a postoperative delirium in a patient during recovery from parathyroidectomy. We noted that the delirium resembled serotonin toxicity and that the patient had been taking paroxetine until 2 days before surgery. We offered several tentative explanations for this event, including an adverse interaction between paroxetine and other agent(s) used in the course of the anaesthesia. Recent developments in characterisation of serotonin toxicity have prompted us to re-examine the clinical details surrounding this life-threatening event. It is now known to be important that the patient was given methylene blue, pre-operatively, to enable visualisation of the parathyroid glands. Methylene blue has been found to be a potent inhibitor of monoamine oxidase (MAO), and several cases of serotonin toxicity have been reported recently following its administration. All these cases are consistent with the well-known risk of serotonin toxicity when drugs that augment serotonergic transmission are given in combination with an MAO inhibitor. Methylene blue is used in a variety of surgical settings as well as for treatment of various types of hypotensive shock and methemoglobinaemia. It is also being studied for treatment of Alzheimer's disease and malaria. In this paper, we outline the pharmacology of methylene blue and the aetiology of serotonin toxicity to help prevent further unintentional co-administration of drugs that risk precipitating this life-threatening drug interaction.

Simvastatin-Induced Rhabdomyolysis Following Cyclosporine Treatment for Uveitis

The purpose of this study was to heighten awareness of a potentially life-threatening drug interaction in patients with chronic uveitis treated with cyclosporine. A 69-year-old female with chronic posterior uveitis was treated with cyclosporine while on concomitant oral simvastatin for hypercholesterolemia. Rhabdomyolysis developed with acute renal failure from the probable interaction between these drugs. Discontinuation of simvastatin and cyclosporine resulted in resolution of rhabdomyolysis and normalization of renal function. Statins are associated with a small, dose-related risk of myopathy, myositis, and rhabdomyolysis. Cyclosporine is a potent inhibitor of simvastatin metabolism, and may therefore facilitate simvastatin-induced rhabdomyolysis. Concomitant use of statins and cyclosporine should be avoided.

Antidepressant Drug-Drug Interaction Profile Update

Drug-drug interactions continue to be underappreciated and misunderstood by most clinicians. Although life-threatening drug interactions are rare, serious clinical consequences, including altered drug response, poor tolerability with reduced medication adherence, and increased costs for care tied to the increased complexity of therapy, are fairly commonplace. Drug interactions may be further complicated by genetic differences in metabolic capacity. Patients who routinely require long-term treatment for depression have an increased likelihood of experiencing a drug-drug interaction since they will take over-the-counter and prescription medications for intercurrent and/or co-morbid illness. Antidepressants can be the object of drug interactions when their metabolic pathways are affected by other substances, or they can precipitate interactions by inhibiting enzyme pathways. Clinicians can improve the short- and long-term outcomes of patients with a depressive disorder by considering the possibility of drug-drug interactions both before prescribing a specific antidepressant and while monitoring for response, adverse effects and patient compliance.

Influence of lipid lowering fibrates on P-glycoprotein activity in vitro

Statin/fibrate combinations are frequently used to treat mixed dyslipidemia. However, these combinations may cause life-threatening drug interactions (e.g. rhabdomyolysis) possibly induced by modifications of cytochrome P450 isozyme activities. Some statins are also transported by P-glycoprotein (Pgp) and may act as inhibitors of this drug efflux pump. So far, nothing is known about possible Pgp modulating effects of fibrates. We tested whether gemfibrozil, fenofibrate, fenofibric acid, and bezafibrate inhibit Pgp in vitro using a calcein acetoxymethylester (calcein-AM) uptake assay and confocal laser scanning microscopy with bodipy-verapamil as substrate in L-MDR1 cells, which overexpress human Pgp. In uptake assays in cells with (L-MDR1) and without (LLC-PK1) human Pgp we also investigated whether these compounds are transported by Pgp. Intracellular concentrations were measured by liquid chromatography tandem mass spectrometry. Of the tested fibrates, only fenofibrate increased calcein-AM uptake into cells indicating an inhibition of Pgp mediated transport by this compound. The potency of fenofibrate (mean±SD: 7.1±3.2 μM), evaluated by calculating the concentration needed to double baseline fluorescence (f2), was similar to that of simvastatin (5.8±1.5 μM), lovastatin (10.1±1.0), and verapamil (4.7±0.8 μM). For simvastatin and fenofibrate Pgp inhibition was confirmed with confocal laser scanning microscopy. Fenofibrate, fenofibric acid, gemfibrozil, and bezafibrate showed no difference in the cellular uptake between LLC-PK1 and L-MDR1, indicating that the tested fibrates are not Pgp substrates. In conclusion, this study demonstrates that fenofibrate inhibits Pgp in vitro with a potency similar to simvastatin.

Characterization of Methotrexate Transport and Its Drug Interactions with Human Organic Anion Transporters

Life-threatening drug interactions are known to occur between methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs), probenecid, and penicillin G. The purpose of this study was to characterize methotrexate transport, as well as to determine the site and the mechanism of drug interactions in the proximal tubule. Mouse proximal tubule cells stably expressing basolateral human organic anion transporters (hOAT1 and hOAT3) and apical hOAT (hOAT4) were established. The K(m) values for hOAT1-, hOAT3-, and hOAT4-mediated methotrexate uptake were 553.8 microM, 21.1 microM, and 17.8 microM, respectively. NSAIDs (salicylate, ibuprofen, ketoprofen, phenylbutazone, piroxicam, and indomethacin), probenecid, and penicillin G dose dependently inhibited methotrexate uptake mediated by hOAT1, hOAT3, and hOAT4. Kinetic analysis of inhibitory effects of these drugs on hOAT3-mediated methotrexate uptake revealed that these inhibitions were competitive. The K(i) values for the effects of salicylate, phenylbutazone, indomethacin, and probenecid on hOAT3-mediated methotrexate uptake were comparable with therapeutically relevant plasma concentrations of unbound drugs. In addition, in the presence of human serum albumin, the K(i) values were comparable with therapeutically relevant total plasma concentrations of drugs. In conclusion, these results suggest that methotrexate is taken up via hOAT3 and hOAT1 at the basolateral side of the proximal tubule and effluxed or taken up at the apical side via hOAT4. In addition, hOAT1, hOAT3, and hOAT4 are the sites of drug interactions between methotrexate and NSAIDs, probenecid, and penicillin G. Furthermore, it was predicted that hOAT3 is the site of drug interactions between methotrexate and salicylate, phenylbutazone, indomethacin, and probenecid in vivo.

Antiparkinsonian agents. Drug interactions of clinical significance.

Within the past 3 decades revolutionary changes have taken place in the pharmacological management of Parkinson's disease. Used alone, or often in combination, antiparkinsonian agents can dramatically and meaningfully ameliorate the symptoms of Parkinson's disease. However, with the development of effective therapeutic agents has come the potential for drug interactions; these interactions can produce consequences that range from the inconsequential to incapacitating and even life-threatening. Drug-drug interactions are not a major problem with either the anticholinergic medications or amantadine. However, cumulative anticholinergic toxicity may occur when multiple drugs with anticholinergic properties are utilised concomitantly, and amantadine toxicity can be triggered by drugs that impair its renal clearance. Gastric emptying and levodopa absorption can be significantly altered by medications and dietary contents. A rather extensive array of medications can interfere with dopaminergic function and thus produce clinical parkinsonism or impair the effectiveness of levodopa. The effectiveness of direct dopamine agonists can also be affected by a small group of agents. As a selective monoamine oxidase type B (MAO-B) inhibitor, selegiline (deprenyl) is free of the 'cheese-effect' when employed in recommended dosages. However, potentially life-threatening drug interactions, with both pethidine (meperidine) and with fluoxetine and other antidepressant medications, have been described, presumably occurring via serotonergic mechanisms. Awareness of the potential for drug interactions with antiparkinsonian agents, and prompt recognition of them when they do occur, is vital for the optimum clinical management of Parkinson's disease.