Harmful Drug-drug Interactions Research Articles

Thiazolidinedione Class of Anti-Diabetic Drugs Modulate Nuclear Receptor CAR Function

The human body has developed a defence system to prevent the accumulation of endogenous (bile acids, steroids, cholesterol metabolites, neurotransmitters, etc.) as well as exogenous (xenobiotics, clinical drugs, etc.) small molecules at toxic levels. This task is accomplished by ‘drug metabolism and disposition (DMD) machinery’ which entails phase I and phase II enzymes, and phase III transporter proteins. The components of this machinery act in a coordinated manner to biotransform and facilitate the elimination of small toxic molecules from the cellular milieu. Constitutive androstane receptor (CAR), a member of the nuclear receptor superfamily, acts as one of the major transcriptional regulators of the DMD machinery. Prescription of combination therapy is a common regimen during the treatment of diverse metabolic disorders and infectious diseases. In such combination therapies one drug may modulate the expression of genes of DMD, influencing the metabolism of another co-administered drug. This leads to decreased bioavailability or increased toxicity of the latter. Evaluation of drug-drug interactions (DDIs) has now become a major safety concern during drug discovery and development processes. Pre-assessment of the small molecules for modulatory effects on CAR and induction of the components of DMD can resolve the safety concerns, treatment failures and drug withdrawals due to the harmful DDIs. In the present study, we have followed a ‘reverse approach’ to assess CAR activation by drugs previously withdrawn from clinical practices. We selected three redundant members of thiazolidinedione family of anti-diabetic drugs and examined their potential in regulation of CAR and its target gene CYP2B6. These drugs showed differential transcriptional activation of CAR. Two of the TZD i.e., rosiglitazone and pioglitazone enhanced CAR activity by behaving as receptor ligands while the other (troglitazone) did not influence the receptor function and was justly withdrawn since it inflicted cytotoxicity.

A study of harmful drug-drug interactions due to polypharmacy in hospitalized patients in Goa Medical College.

Introduction:Concomitant use of multiple drugs is often indicated to manage comorbid conditions and enhance efficacy. Such concomitant use of multiple drugs (five or more drugs) has been defined as “polypharmacy.” Polypharmacy has been associated with adverse consequences such as greater healthcare costs, increased risk of adverse drug events, drug–drug interactions (DDIs), medication nonadherence, reduced functional capacity, and multiple geriatric syndromes. This study evaluated number of potential harmful DDIs due to polypharmacy.Materials and Methods:A prospective, cross-sectional, observational study was performed from July 2011 to June 2012. Approval was obtained from the Institutional Ethics Committee, Goa Medical College. Drug interactions were identified using a computerized DDI database system Lexi-Comp version: 2.4.1. Quantitative data analysis was done by the SPSS for Windows version 17.0.Results:Seven hundred and fifty-one out of 5424 (13.85%) prescriptions were observed to have polypharmacy with highest rates observed in the Department of Medicine. The median age of patients was 55.60 ± 13.86 (range 10–108 years). A total number of drugs per prescription ranged from minimum of 5 to maximum of 16 drugs, with an average of 7.96 ± 1.75. A large number of 596 prescriptions contained 6–9 drugs per prescription. Drugs involved in potential DDIs in our study included aspirin, antacids, beta-blockers, 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors, calcium channel blockers, angiotensin-converting enzyme inhibitors, ondansetron, and H2 blockers.Conclusion:Patients taking multiple medications experience unique pharmacotherapy. Personalized drug prescribing strategies and close monitoring of patients taking drugs with potential DDIs are keys to optimal therapeutic result.

Comorbidities and pharmacotherapies in patients with Gaucher disease type 1: The potential for drug-drug interactions.

Clinical care for patients with rare diseases may be complicated by comorbidities. Administration of medications to treat comorbidities may elicit potentially harmful drug-drug interactions (DDIs). Genetic background may also influence DDI occurrence. We investigated the range of comorbid conditions in patients with Gaucher disease type I (GD1), the pharmacotherapies prescribed and the potential for DDI with enzyme replacement and substrate reduction therapies and additional medications, specifically cytochrome P450 (CYP) metabolizing medications. A literature review examined comorbid conditions and pharmacotherapies reported in GD1. Analysis of two national databases reported real-world prescription practices in patients with GD1 (Germany, N=87; US, N=374). Prescribed drugs were assessed for known interactions with isoenzymes from the hepatic CYP enzyme family. The literature reported GD1 symptomatology and comorbid conditions in broad agreement with the known clinical picture. German patients received 86 different medications whereas US patients received 329 different medications. An average of 3.2 medications (Germany) and 7 medications (US) per patient were prescribed. Moderate/strong inhibitors of CYP isoenzymes were prescribed to 20% and 57% of patients in the US and Germany, respectively. This study describes the extensive number of comorbid conditions and drugs prescribed to patients with GD1, and the importance of determining CYP isoenzyme interaction to reduce DDI risk.

Inhibition of human cytochrome P450 isoenzymes by a phenothiazine neuroleptic levomepromazine: An in vitro study.

Inhibition of cytochrome P450 (CYP) isoenzymes is the most common cause of harmful drug-drug interactions. The present study was aimed at examining the inhibitory effect of the phenothiazine neuroleptic levomepromazine on main CYP isoenzymes in human liver. The experiment was performed in vitro using the human cDNA-expressed CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 (Supersomes). CYP isoenzyme activities were determined using the CYP-specific reactions: caffeine 3-N-demethylation (CYP1A2), diclofenac 4'-hydroxylation (CYP2C9), perazine N-demethylation (CYP2C19), bufuralol 1'-hydroxylation (CYP2D6) and testosterone 6β-hydroxylation (CYP3A4). The rates of the CYP-specific reactions were assessed in the absence and presence of levomepromazine (1-50 μM). The concentrations of CYP-specific substrates and their metabolites formed by CYP isoenzymes were measured by HPLC with UV or fluorimetric detection. Levomepromazine potently inhibited CYP2D6 (K(i) = 6 μM) in a competitive manner. Moreover, the neuroleptic moderately diminished the activity of CYP1A2 (K(i) = 47 μM) and CYP3A4 (K(i) = 34 μM) via a mixed mechanism. On the other hand, levomepromazine did not affect the activities of CYP2C9 and CYP2C19. The inhibition of CYP1A2, CYP2D6 and CYP3A4 by levomepromazine, demonstrated in vitro in the present study, should also be observed in vivo (especially the CYP2D6 inhibition by levomepromazine), since the calculated K(i) values are below or close to the presumed concentration range for levomepromazine in the liver in vivo. Therefore pharmacokinetic interactions involving levomepromazine and CYP2D6, CYP1A2 or CYP3A4 substrates are likely to occur in patients during co-administration of the above-mentioned substrates/drugs.

Frequency, types and factors associated with potentially harmful drug interactions in ambulatory elderly patients in Nigeria.

To determine the frequency, types and factors associated with potentially harmful drug interactions among ambulatory elderly (≥65 years) patients in Ibadan, Nigeria. A 4-week cross-sectional study was conducted among 229 elderly patients who consented and were prescribed two or more medicines within a 4-week study period at a major 256-bed secondary care facility in Ibadan, Nigeria. Chi-square and risk ratio were used to identify the factors associated with the potentially harmful drug-drug interactions. Potentially harmful drug-drug interactions were identified in about two-thirds (65%, 149/229) of the patients. The risk of occurrence drug interactions was significantly higher among patients who had at least six prescribed medicines (relative risk: 7.8 (95% confidence interval, 6.9 to 9.5) (P < 0.001)), and a significant majority were also females (73.8%) (110) (P < 0.001). The most frequent interacting drug combination was angiotensin-converting enzyme inhibitors and amiloride + hydrochlorothiazide (34.7%). Potentially harmful drug interactions that are significantly associated with high multiple prescribing are considerable among elderly patients in Nigeria.

Anti-hypertensive medicines prescribing for medical outpatients in a premier teaching hospital in Nigeria: a probable shift of paradigm.

Previous studies of anti-hypertensive medicines utilization pattern in Nigeria showed that Angiotensin converting enzyme inhibitors (ACEIs) were often the least prescribed. However, the appropriate use of ACEIs in the black population achieves good blood pressure control and provides additional long term cardio- and renovascular protection benefits. To assess the current utilization pattern of antihypertensive medicines with specific emphasis on identifying possible shift in the frequency of use of ACEIs. A prospective cross-sectional assessment of the current utilization pattern of anti-hypertensive medicines was conducted among 300 randomly selected cohort at a 900-bed premier Teaching Hospital located in Ibadan, Southwestern Nigeria. The current utilization pattern was compared with the results of a study conducted at the same site and published 10 years ago. Of the 300 random cohorts, a majority (79%) were females (237) with mean age 58.7 years (SD=2.81 years. Stage 2 hypertension was the most frequent diagnosis (54.3%). The utilization of ACEIs and long acting CCB (amlodipine) significantly increased from 8.6% and 21% (Ten years ago) to 29.93% and 36.68% respectively (p < 0.0001). The use of thiazide diuretic and methyldopa declined significantly from 39.4% and 23.3% (Ten years ago) to 16.12% and 9.7% respectively (p < 0.0001). Adverse drug reactions due to ACEIs were documented in 1.5% (3), while laboratory monitoring of serum potassium, urea and creatinine was conducted in only 37% (111) of cohort. Potentially harmful drug-drug interactions were identified in 25% (75) of cohorts, and the most frequent were ACEIs + NSAIDs (53.3%), ACEIs + amiloride / hydrochlorothiazide (22.6%). Anti-hypertensive medicines utilization has significantly shifted towards the increased use of ACEIs and long acting dihydropyridine CCBs. The use of thiazides and methyldopa has declined significantly. Physicians appeared more cognizant of the long term cardio- and renovascular benefits inherent in using ACEIs in a high cardiovascular risk group such as black hypertensive.

Computer-based adverse drug effects monitoring systems and the impact on patients' outcomes: A literature overview

With the growing number of older persons, the intake of multiple medications due to multimorbidity is challenging. Polypharmacy may result in harmful drug-drug interaction. In Germany older people living in nursing homes often ingest more than nine active components per day. This results in 4.6 adverse drug effects (ADE) per 100 resident months. ADE lead to an increased risk of fall, cause increased hospital admissions and are blamed for more than 100,000 deaths per year in the US. Generally, computer based monitoring systems are increasingly applied to reduce ADE. However, an overview of direct effects of their use on patients'/residents' health related outcomes (e.g. quality of life, apathy) is lacking yet. Therefore this study aims to provide an overview of available knowledge on beneficial aspects of computer-based ADE monitoring systems. A comprehensive systematic literature research was conducted in 2012 including the electronic databases: Carelit, Gerolit, Cinahl, PsychInfo, and Pubmed. The sensitive retrieval strategy included the terms “adverse drug reaction” AND “computer*” AND “care.” English and German publications were included into the review. Included papers had to report effects of computer-based ADE monitoring systems on patients'/residents' health outcomes and/or costs. Based upon Cochrane Collaboration Guidelines the included papers were evaluated concerning their quality. The initial search yielded 161 publications. After screening title and abstract, 12 publications were included in the further analysis. Most excluded publications contained the searching terms, but did not contribute to answer the research question. Publications showed an average quality. Computer-based ADE monitoring systems can successfully be implemented in daily practice of hospitals and nursing homes. To be beneficial, physicians and nurses had to be accepted these systems. Several studies showed positive effects, including reduced re-admission rates to hospitals, medication costs and mortality rates compared to external control groups. No study is reporting effects on patients'/residents' health related outcomes. Computer-based ADE monitoring systems show benefits in the care of patients/residents. However, there is a lack of knowledge, whether they contribute to improved health-related outcomes of patients. Therefore, further research concentrated on the impact of Computer-based ADE monitoring systems on patients'/ residents' health outcomes is required.

Inhibitory effects of sanguinarine on human liver cytochrome P450 enzymes

Sanguinarine (SAG) has been recognized as an anticancer drug candidate. However, the drug-drug interactions (DDI) potential for SAG via the inhibition against human cytochrome P450 (CYP) enzymes remains unclear. In the present study, the inhibitory effects of SAG on seven major human CYP isoforms 1A2, 2A6, 2E1, 2D6, 2C8, 2C9 and 3A4 were investigated with human liver microsomes (HLM). The results showed that SAG was a potent noncompetitive inhibitor of CYP2C8 activity (Ki=8.9 μM), and competitive inhibitor of CYP1A2, CYP2C9 and CYP3A4 activities (Ki=2.7, 3.8 and 2.0 μM, respectively). Furthermore, SAG exhibited time- and NADPH-dependent inhibition towards CYP1A2 and CYP3A4 with KI/kinact values of 13.3/0.087 and 5.58/0.029 min(-1) μM(-1), respectively. Weak inhibition of SAG against CYP2E1, CYP2D6 and CYP2A6 was also observed. In vitro-in vivo extrapolation (IV-IVE) from HLM data showed that more than 35.9% of CYP1A2, CYP2C9, CYP2C8 and CYP3A4 activities in vivo could be inhibited by SAG, suggesting that harmful DDIs could occur when SAG or its medical preparations are co-administered with drugs primarily cleared by these CYP isoforms. Further in vivo studies are needed to evaluate the clinical significance of the data presented herein.

Arzneimittelinteraktionen in der Psychiatrie

In daily practice of psycho-pharmacotherapy most patients are under polypharmacy which may result in potentially harmful drug-drug interactions. Therefore, we investigated if the risk of drug-drug interactions can be reduced by a consultant clinical pharmacist for the physicians on psychiatric wards. Drug-drug-interactions and adverse drug reactions of patients on 2 psychiatric intensive care units were investigated retrospectively in 2008 and 2009. Before the second investigation period, a special training was performed and during this period a pharmacist supported the physicians regarding drug therapy. After the introduction of a pharmacist on the ward and 2 teaching lessons relevant drug interactions were reduced by 78 % (p < 0.001), the number of all interactions by 44 % (p < 0.001). The total number of drug interactions decreased by the training sessions, which were offered shortly before starting the second observation period, from 3.4 interactions/patients in 2008 to 2.2 interactions/patients in 2009 (p < 0.04). A clinical pharmacist on the ward can contribute to a higher drug therapy safety in psychiatric wards. An interdisciplinary approach can relieve the physicians' daily work. The drug therapy can be improved by continuous teaching sessions about drug interactions.

Exposure to Potentially Dangerous Drug-Drug Interactions Involving Antipsychotics

Antipsychotic drug therapy is the cornerstone of treatment of persons with schizophrenia. Because most antipsychotics are metabolized by the hepatic cytochrome P450 system, concomitant use of an antipsychotic and medications that are competitively metabolized by the same system may cause a potentially harmful drug-drug interaction. This study used a large state's Medicaid claims database to examine the proportion of patients exposed to such interactions and the risk factors associated with exposure. Claims from January 2000 through December 2003 for adult patients with a diagnosis of schizophrenia and at least one prescription for an antipsychotic (N=27,909) were examined for pairs of medications identified as potentially causing moderate or severe adverse drug effects. Logistic regression models were estimated to determine potential risk factors associated with exposure to the interaction pairs. A total of 6,417 (23%) patients were exposed to 14,213 potentially harmful interactions; 4,725 patients had at least one exposure from the same pharmacy, and 4,032 patients were exposed by the same physician. The greatest number of exposures (N=1,353) to potentially harmful combinations involved olanzapine and haloperidol. Patients prescribed risperidone were most likely to be exposed to an interaction (13.1%), followed by patients prescribed olanzapine (10.3%), quetiapine (3.3%), and clozapine (3.2%). A higher risk of exposure was associated with being female (odds ratio [OR]=.94), being white (OR=1.43), having depression (OR=1.21), or having impulse-control disorder (OR=1.98). Interventions by physicians and pharmacies to reduce the prescribing and dispensing of potentially harmful pairs of medications to patients with schizophrenia are recommended.

Clarity and Applicability of Drug-Drug Interaction Management Guidelines

Despite the availability and daily use of computerized drug-drug interaction surveillance systems, exposure to potentially relevant drug-drug interactions (DDIs) continues. DDI management guidelines are often inadequate and clear management options are lacking, which attributes to overriding of DDI signals. Although general criteria for the development and reporting of high-quality clinical practice guidelines have been identified, it appears these have not yet been applied to DDI management guidelines. The aim of the study was to assess the clarity and applicability of guidelines for the management of potentially harmful DDIs. We selected 13 DDIs that are potentially harmful for patients and frequently occur in community pharmacy practice in the Netherlands. The clarity and applicability of the management guidelines of these DDIs were appraised using the appropriate two domains - 'Clarity and presentation' and 'Applicability', of the validated Appraisal of Guidelines for Research and Evaluation (AGREE) Instrument. The appraisal was performed by 12 community pharmacists and 12 general practitioners. The standardized domain scores and mean item scores for 'Clarity and presentation' and 'Applicability' were compared. All DDI management guidelines were generally found to score well on 'Clarity and presentation', but poorly with respect to 'Applicability' (standardized domain scores 68.0 vs 26.1%). Within the domain 'Clarity and presentation', the item 'tools for application' received the lowest scores. Within the domain 'Applicability', cost implications, organizational barriers and key review criteria were all poorly documented. All guidelines presented non-directive advice using words such as 'consider' and 'regularly'. Developers of DDI management guidelines should take the appropriate domains of the AGREE Instrument into consideration in their development processes. The applicability of DDI management guidelines should be pretested before publishing. To improve guideline quality, more attention should particularly be paid to the available tools for applications and cost implications.

Harnessing the internet cloud for managing drug interactions with chemotherapy regimens in patients with cancer suffering from depression

Concomitant use of anticancer drugs (ACDs) and antidepressants (ADs) in the treatment of depression in patients with cancer may result in potentially harmful drug-drug interactions (DDIs). It is crucial that clinicians make timely, accurate, safe and effective decisions regarding drug therapies in patients. The ubiquitous nature of the internet or “cloud” has enabled easy dissemination of DDI information, but there is currently no database dedicated to allow searching of ACD interactions by chemotherapy regimens. We describe the implementation of an AD interaction module to a previously published oncology-specific DDI database for clinicians which focuses on ACDs, single-agent and multiple-agent chemotherapy regimens. Methods. Drug- and DDI-related information were collated from drug information handbooks, databases, package inserts, and published literature from PubMed, Scopus and Science Direct. Web documents were constructed using Adobe software and programming scripts, and mounted on a domain served from the internet cloud. Results. OncoRx is an oncology-specific DDI database whose structure is designed around all the major classes of ACDs and their frequently prescribed chemotherapy regimens. There are 117 ACDs and 256 regimens in OncoRx, and it can detect over 1 500 interactions with 21 ADs. Clinicians are provided with the pharmacokinetic parameters of the drugs, information on the regimens and details of the detected DDIs during an interaction search. Conclusion. OncoRx is the first database of its kind which allows detection of ACD and chemotherapy regimen interactions with ADs. This tool will assist clinicians in improving clinical response and reducing adverse effects based on the therapeutic and toxicity profiles of the drugs.

Cardiovascular drug interactions with tyrosine kinase inhibitors

Summary Imatinib mesylate, a selective inhibitor of tyrosine kinases, has excellent efficacy in the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST). Inducing durable responses and achieving prolonged survival, it has become the standard of care for the treatment of these diseases. It has opened the way to the development of additional tyrosine kinase inhibitors (TKIs), including sunitinib, nilotinib, dasatinib and sorafenib, all indicated for the treatment of various haematological malignancies and solid tumours. TKIs are prescribed for prolonged periods and are often taken by patients with – notably cardiovascular – comorbidities. Hence TKIs are regularly co-administered with cardiovascular drugs, with a considerable risk of potentially harmful drug-drug interactions due to the large number of agents used in combination. However, this aspect has received limited attention so far, and a comprehensive review of the published data on this important topic has been lacking. We review here the available data and pharmacological mechanisms of interactions between commonly prescribed cardiovascular drugs and the TKIs marketed at present. Regular updating of the literature on this topic will be mandatory, as will the prospective reporting of unexpected clinical observations, given the fact that these drugs have been only recently marketed.

Structural basis of human pregnane X receptor activation by the hops constituent colupulone.

Hops extracts are used to alleviate menopausal symptoms and as an alternative to hormone replacement therapy, but they can produce potentially harmful drug-drug interactions. The nuclear xenobiotic receptor pregnane X receptor (PXR) is promiscuously activated by a range of structurally distinct chemicals. It has a key role in the transcriptional regulation of genes that encode xenobiotic metabolism enzymes. In this study, hops extracts are shown to induce the expression of numerous drug metabolism and excretion proteins. The beta-bitter acid colupulone is demonstrated to be a bioactive component and direct activator of human PXR. The 2.8-A resolution crystal structure of the ligand binding domain of human PXR in complex with colupulone was elucidated, and colupulone was observed to bind in a single orientation stabilized by both van der Waals and hydrogen bonding contacts. The crystal structure also indicates that related alpha- and beta-bitter acids have the capacity to serve as PXR agonists as well. Taken together, these results reveal the structural basis for drug-drug interactions mediated by colupulone and related constituents of hops extracts.

Many prescribers may not recognise potentially harmful drug-drug interactions,

Many prescribers may not recognise potentially harmful drug-drug interactions,

Antidepressant Drug-Drug Interactions: Clinical Relevance and Risk Management

AbstractMultiple medication use is a common phenomenon, especially in patients with comorbid conditions and those treated with psychiatric drugs such as antidepressants. Combination treatment may result in potentially harmful drug-drug interactions (DDIs). Results of DDIs range from nuisance side effects to serious adverse consequences. DDIs may also result in improved efficacy. Augmentation strategies, for example, are intentional therapeutic DDIs. Pharmacokinetic DDIs occur when a second drug alters the absorption, distribution, metabolism, or clearance of the first drug. Research has concentrated on the relative effects of antidepressants on cytochrome P450 enzymes and, more recently, on drug transporters as potential mediators of clinically important pharmacokinetic DDIs. The most common, clinically relevant pharmacokinetic DDIs involve alteration in oxidative drug metabolism. Pharmacodynamic DDIs occur when the effects of a second drug quantitatively or qualitatively alters those of the first drug. Pharmacodynamic DDIs are not typically studied in vivo because of the potential for a serious adverse effect. All antidepressants can interact pharmacodynamically with certain other drugs. The risk of harmful DDIs can be reduced by recognizing variables that affect dose-concentration-effect relationships. It is important for physicians to weigh the risks and benefits of potential DDIs against the risks that accompany timid or ineffective disease treatment.

The constitutive androstane receptor mediates phenytoin induction of cyp2c37

Cytochrome P450 monoxygenases (P450) are responsible for the metabolism and detoxification of many therapeutics. Induction of P450 enzymes by drugs can lead to potentially harmful drug-drug interactions and alterations in drug therapy efficacy. Drug induction of P450 enzymes has been shown to involve the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR). Recently, we reported that the nuclear receptor CAR mediated phenytoin (DPH) induction of the murine Cyp2b10 and Cyp2c29 genes. Herein, we report the discovery of a second DPH inducible murine CYP2C, Cyp2c37. Quantitative RT-PCR and immunoblot data demonstrate that hepatic CYP2C37 mRNA and protein amounts are increased by DPH. We have identified a putative CAR response element (CAR-RE) at -2.8kb from the start of translation of the Cyp2c37 gene. Mutation of this CAR-RE in Cyp2c37 luciferase promoter constructs demonstrated that it is necessary for mCAR constitutive transactivation and that induction is governed by a transcriptional regulation mechanism. Furthermore in CAR-null mice, quantitative RT-PCR results indicate that the induction of CYP2C37 mRNA by DPH is abolished. These results suggest that DPH induction of the Cyp2c37 gene, like the Cyp2b10 and Cyp2c29 genes, is regulated by mCAR. However, in CAR-null mice induction of CYP3A11 mRNA is not abolished suggesting that both CAR and PXR can mediate DPH induction of P450 genes, depending on the gene promoter. This research was supported by the intramural division of the NIEHS.

The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism.

The nuclear pregnane X receptor (PXR; NR1I2) is an important component of the body's adaptive defense mechanism against toxic substances including foreign chemicals (xenobiotics). PXR is activated by a large number of endogenous and exogenous chemicals including steroids, antibiotics, antimycotics, bile acids, and the herbal antidepressant St. John's wort. Elucidation of the three-dimensional structure of the PXR ligand binding domain revealed that it has a large, spherical ligand binding cavity that allows it to interact with a wide range of hydrophobic chemicals. Thus, unlike other nuclear receptors that interact selectively with their physiological ligands, PXR serves as a generalized sensor of hydrophobic toxins. PXR binds as a heterodimer with the 9-cis retinoic acid receptor (NR2B) to DNA response elements in the regulatory regions of cytochrome P450 3A monooxygenase genes and a number of other genes involved in the metabolism and elimination of xenobiotics from the body. Although PXR evolved to protect the body, its activation by a variety of prescription drugs represents the molecular basis for an important class of harmful drug-drug interactions. Thus, assays that detect PXR activity will be useful in developing safer prescription drugs.

Pharmacokinetic interactions between erythromycin, clarithromycin, roxithromycin and phenytoin in the rat.

The effects of the macrolide antibiotics, erythromycin, clarithromycin and roxithromycin, on the pharmacokinetic profile of phenytoin were studied in rats. Animals were injected with phenytoin (100 mg/kg, i.p.) daily for 4 days and then they were given phenytoin (20 mg/kg, i.p.) alone or the same dose of phenytoin together with erythromycin (50 mg/kg, i.p.), clarithromycin (50 mg/kg, i.p.) or roxithromycin (50 mg/kg, i.p.). In another set of experiments, the same protocol was followed except that erythromycin (100 mg/kg), clarithromycin (100 mg/kg) and roxithromycin (100 mg/kg) were given by the oral route. The concentrations of phenytoin in plasma were determined using a high-performance liquid chromatographic method. The area under the curve the maximum plasma concentration and the elimination half-life (t1/2) of phenytoin were significantly (p < 0.05) increased by the macrolides. In addition, the macrolides significantly (p < 0.05) reduced the level of hepatic cytochrome P-450 in the rats. These results suggest that a potentially harmful drug-drug interaction may occur if phenytoin is administered concurrently with erythromycin, clarithromycin or roxithromycin.

Diltiazem and verapamil elevate plasma phenytoin concentrations in the rat

The effects of the calcium channel blockers, diltiazem and verapamil on the pharmacokinetics of phenytoin were investigated in rats. Animals were given phenytoin alone or phenytoin together with either diltiazem or verapamil and the plasma samples were collected at different time intervals. The concentration of phenytoin was measured using a high performance liquid chromatographic method (HPLC). Diltiazem and verapamil significantly ( p < 0.05) increased the area under the curve (AUC), the maximum plasma concentration ( C max) and elimination half+life ( t 1:2) of phenytoin. These results suggest that a potentially harmful drug-drug interaction may occur if phenytoin is administered concurrently with either diltiazem or verapamil.