Drug-drug interactions of antifungal agents and implications for patient care

Drug interactions in the gastrointestinal tract, liver and kidneys result from alterations in pH, ionic complexation, and interference with membrane transport proteins and enzymatic processes involved in intestinal absorption, enteric and hepatic metabolism, renal filtration and excretion. Azole antifungals can be involved in drug interactions at all the sites, by one or more of the above mechanisms. Consequently, azoles interact with a vast array of compounds. Drug-drug interactions associated with amphotericin B formulations are predictable and result from the renal toxicity and electrolyte disturbances associated with these compounds. The echinocandins are unknown cytochrome P450 substrates and to date are relatively devoid of significant drug-drug interactions. This article reviews drug interactions involving antifungal agents that affect other agents and implications for patient care are highlighted.     

Effects of the antifungal agents on oxidative drug metabolism: clinical relevance

This article reviews the metabolic pharmacokinetic drug-drug interactions with the systemic antifungal agents: the azoles ketoconazole, miconazole, itraconazole and fluconazole, the allylamine terbinafine and the sulfonamide sulfamethoxazole. The majority of these interactions are metabolic and are caused by inhibition of cytochrome P450 (CYP)-mediated hepatic and/or small intestinal metabolism of coadministered drugs. Human liver microsomal studies in vitro, clinical case reports and controlled pharmacokinetic interaction studies in patients or healthy volunteers are reviewed. A brief overview of the CYP system and the contrasting effects of the antifungal agents on the different human drug-metabolising CYP isoforms is followed by discussion of the role of P-glycoprotein in presystemic extraction and the modulation of its function by the antifungal agents. Methods used for in vitro drug interaction studies and in vitro-in vivo scaling are then discussed, with specific emphasis on the azole antifungals. Ketoconazole and itraconazole are potent inhibitors of the major drug-metabolising CYP isoform in humans, CYP3A4. Coadministration of these drugs with CYP3A substrates such as cyclosporin, tacrolimus, alprazolam, triazolam, midazolam, nifedipine, felodipine, simvastatin, lovastatin, vincristine, terfenadine or astemizole can result in clinically significant drug interactions, some of which can be life-threatening. The interactions of ketoconazole with cyclosporin and tacrolimus have been applied for therapeutic purposes to allow a lower dosage and cost of the immunosuppressant and a reduced risk of fungal infections. The potency of fluconazole as a CYP3A4 inhibitor is much lower. Thus, clinical interactions of CYP3A substrates with this azole derivative are of lesser magnitude, and are generally observed only with fluconazole dosages of > or =200 mg/day. Fluconazole, miconazole and sulfamethoxazole are potent inhibitors of CYP2C9. Coadministration of phenytoin, warfarin, sulfamethoxazole and losartan with fluconazole results in clinically significant drug interactions. Fluconazole is a potent inhibitor of CYP2C19 in vitro, although the clinical significance of this has not been investigated. No clinically significant drug interactions have been predicted or documented between the azoles and drugs that are primarily metabolised by CYP1A2, 2D6 or 2E1. Terbinafine is a potent inhibitor of CYP2D6 and may cause clinically significant interactions with coadministered substrates of this isoform, such as nortriptyline, desipramine, perphenazine, metoprolol, encainide and propafenone. On the basis of the existing in vitro and in vivo data, drug interactions of terbinafine with substrates of other CYP isoforms are unlikely.     

Antiarrhythmic agents: drug interactions of clinical significance.

The management of cardiac arrhythmias has grown more complex in recent years. Despite the recent focus on nonpharmacological therapy, most clinical arrhythmias are treated with existing antiarrhythmics. Because of the narrow therapeutic index of antiarrhythmic agents, potential drug interactions with other medications are of major clinical importance. As most antiarrhythmics are metabolised via the cytochrome P450 enzyme system, pharmacokinetic interactions constitute the majority of clinically significant interactions seen with these agents. Antiarrhythmics may be substrates, inducers or inhibitors of cytochrome P450 enzymes, and many of these metabolic interactions have been characterised. However, many potential interactions have not, and knowledge of how antiarrhythmic agents are metabolised by the cytochrome P450 enzyme system may allow clinicians to predict potential interactions. Drug interactions with Vaughn-Williams Class II (beta-blockers) and Class IV (calcium antagonists) agents have previously been reviewed and are not discussed here. Class I agents, which primarily block fast sodium channels and slow conduction velocity, include quinidine, procainamide, disopyramide, lidocaine (lignocaine), mexiletine, flecainide and propafenone. All of these agents except procainamide are metabolised via the cytochrome P450 system and are involved in a number of drug-drug interactions, including over 20 different interactions with quinidine. Quinidine has been observed to inhibit the metabolism of digoxin, tricyclic antidepressants and codeine. Furthermore, cimetidine, azole antifungals and calcium antagonists can significantly inhibit the metabolism of quinidine. Procainamide is excreted via active tubular secretion, which may be inhibited by cimetidine and trimethoprim. Other Class I agents may affect the disposition of warfarin, theophylline and tricyclic antidepressants. Many of these interactions can significantly affect efficacy and/or toxicity. Of the Class III antiarrhythmics, amiodarone is involved in a significant number of interactions since it is a potent inhibitor of several cytochrome P450 enzymes. It can significantly impair the metabolism of digoxin, theophylline and warfarin. Dosages of digoxin and warfarin should empirically be decreased by one-half when amiodarone therapy is added. In addition to pharmacokinetic interactions, many reports describe the use of antiarrhythmic drug combinations for the treatment of arrhythmias. By combining antiarrhythmic drugs and utilising additive electrophysiological/pharmacodynamic effects, antiarrhythmic efficacy may be improved and toxicity reduced. As medication regimens grow more complex with the aging population, knowledge of existing and potential drug-drug interactions becomes vital for clinicians to optimise drug therapy for every patient.     

Antifolates as antimycotics?: Connection between the folic acid cycle and the ergosterol biosynthesis pathway in Candida albicans

The increased incidence of invasive mycoses and the emerging problem of antifungal drug resistance have encouraged the search for new antifungal agents or effective combinations of existing drugs. Infections due to Candida albicans are usually treated with azole antifungals such as fluconazole, ketoconazole or itraconazole. Whilst azoles may have little or no toxicity, they generally offer rather poor fungicidal activity. Even in the absence of resistance, treatment failures or recurrent infections are not uncommon, especially in immunocompromised individuals. Here we demonstrate that the non-classical antifolate pyrimethamine shows synergy with azole antifungal compounds and interferes with the ergosterol biosynthesis pathway in C. albicans. By disturbing folate metabolism in this fungus, pyrimethamine can inhibit ergosterol production. The molecular connection between the folic acid cycle and the ergosterol biosynthesis pathway is discussed and we show that the filamentous form of this fungus is more susceptible to methotrexate than the yeast form because the drug is more effectively transported through the membrane of the filamentous form. When used to treat the hyphal form, methotrexate showed synergy with other antifungals such as azoles and terbinafine. This finding could have important clinical applications, as a combination of azoles with antifolates and/or inhibitors of folic acid synthesis could represent an attractive alternative for the treatment of C. albicans infections.     

Drug interactions during therapy with three major groups of antimicrobial agents

This review focuses on drug-drug interactions with three major groups of antimicrobial agents: macrolides (including azalides and ketolides), quinolones, which are widely used for the treatment of bacterial infections, and azoles, which are used for antifungal therapy. Macrolides and the ketolide telithromycin are potent inhibitors of CYP3A4 and thus interfere with the pharmacokinetics of many other drugs that are metabolised by this enzyme. In contrast, although closely related, azithromycin is not a cytochrome inhibitor. All quinolones form complexes with di- and trivalent cations and, therefore, the absorption of quinolones can be dramatically reduced when given concomitantly with mineral antacids, zinc or iron preparations. Ciprofloxacin exhibits an inhibitory potential for the cytochrome isoenzyme 1A2, resulting in an inhibition of theophylline metabolism. Other quinolones, such as levofloxacin or moxifloxacin, do not interfere with theophylline metabolism. The systemic azoles, such as ketoconazole, itraconazole, fluconazole and voriconazole, are inhibitors of CYP isoenzymes, such as CYP3A4, CYP2C9 and CYP2C19, to varying degrees. In addition, some are substrates of the MDR-1 gene product, P-glycoprotein. These features are the basis for most of the interactions occurring during azole therapy (e.g., in severely ill patients in the hospital who are treated with multiple drugs).     

Factors influencing the magnitude and clinical significance of drug interactions between azole antifungals and select immunosuppressants

The magnitude of drug interactions between azole antifungals and immunosuppressants is drug and patient specific and depends on the potency of the azole inhibitor involved, the resulting plasma concentrations of each drug, the drug formulation, and interpatient variability. Many factors contribute to variability in the magnitude and clinical significance of drug interactions between an immunosuppressant such as cyclosporine, tacrolimus, or sirolimus and an antifungal agent such as ketoconazole, fluconazole, itraconazole, voriconazole, or posaconazole. By bringing similarities and differences among these agents and their potential interactions to clinicians' attention, they can appreciate and apply these findings in a individualized patient approach rather than follow only the one-size-fits-all dosing recommendations suggested in many tertiary references. Differences in metabolism and in the inhibitory potency of cytochrome P450 3A4 and P-glycoprotein influence the onset, magnitude, and resolution of drug interactions and their potential effect on clinical outcomes. Important issues are the route of administration and the decision to preemptively adjust dosages versus intensive monitoring with subsequent dosage adjustments. We provide recommendations for the concomitant use of these agents, including suggestions regarding contraindicated combinations, those best avoided, and those requiring close monitoring of drug dosages and plasma concentrations.     

Interactions of imidazole antifungal agents with purified cytochrome P-450 proteins

The imidazole N-substituted antifungal agents ketoconazole, miconazole and clotrimazole have been shown to be potent inhibitors of oxidative metabolism by both a phenobarbital-induced cytochrome P-450 (P-450b) and a 3-methylcholanthrene-induced cytochrome P-448-protein (P-450c) in reconstituted systems. All three compounds inhibited the cytochrome P-450b-dependent 7-pentoxyresorufin-O-dealkylase and the cytochrome P-450c-dependent 7-ethoxyresorufin-O-deethylase activities. When 7-benzyloxyresorufin and 7-ethoxycoumarin were employed as substrates with both cytochrome preparations, all three antifungal compounds exhibited selective inhibition of the cytochrome P-450b preparation; ketoconazole was always the weakest inhibitor. The three antifungal agents were also shown to elicit a type II difference spectral interaction with both isoenzymes, the magnitude of the spectral interaction being greater with the cytochrome P-450b preparation.     

Drug delivery strategies for improved azole antifungal action

Background: Azole antifungal agents are the most commonly used antifungals in clinical treatment of both superficial and systemic fungal infections. Many azoles are poorly water soluble, which limits their bioavailability and antifungal effects. Objective: To improve the efficacy of azole antifungal drugs by advances in drug delivery. Methods: Manipulation of drug formulations and administration routes to improve the antifungal pharmacokinetics with targeted delivery, rapidly followed by sustained release and prolonged retention of high drug concentration localized at the infection site. Results/conclusion: Formulation and drug delivery strategies can improve the aqueous wetting and dissolution properties by increasing their chemical potential, stabilizing the drug delivery system and targeting high concentration of the azoles to the infection sites, therefore enhancing the bioavailability and therapeutic efficacy of azole antifungals.     

Frequency of potential azole drug-drug interactions and consequences of potential fluconazole drug interactions

PURPOSE: To assess the frequency of potential azole-drug interactions and consequences of interactions between fluconazole and other drugs in routine inpatient care. METHODS: We performed a retrospective cohort study of hospitalized patients treated for systemic fungal infections with an oral or intravenous azole medication between July 1997 and June 2001 in a tertiary care hospital. We recorded the concomitant use of medications known to interact with azole antifungals and measured the frequency of potential azole drug interactions, which we considered to be present when both drugs were given together. We then performed a chart review on a random sample of admissions in which patients were exposed to a potential moderate or major drug interaction with fluconazole. The list of azole-interacting medications and the severity of interaction were derived from the DRUGDEX System and Drug Interaction Facts. RESULTS: Among the 4,185 admissions in which azole agents (fluconazole, itraconazole or ketoconazole) were given, 2,941 (70.3%) admissions experienced potential azole-drug interactions, which included 2,716 (92.3%) admissions experiencing potential fluconazole interactions. The most frequent interactions with potential moderate to major severity were co-administration of fluconazole with prednisone (25.3%), midazolam (17.5%), warfarin (14.7%), methylprednisolone (14.1%), cyclosporine (10.7%) and nifedipine (10.1%). Charts were reviewed for 199 admissions in which patients were exposed to potential fluconazole drug interactions. While four adverse drug events (ADEs) caused by fluconazole were found, none was felt to be caused by a drug-drug interaction (DDI), although in one instance fluconazole may have contributed. CONCLUSIONS: Potential fluconazole drug interactions were very frequent among hospitalized patients on systemic azole antifungal therapy, but they had few apparent clinical consequences.     

Drug interactions during therapy with three major groups of antimicrobial agents

This review focuses on drug–drug interactions with three major groups of antimicrobial agents: macrolides (including azalides and ketolides), quinolones, which are widely used for the treatment of bacterial infections, and azoles, which are used for antifungal therapy. Macrolides and the ketolide telithromycin are potent inhibitors of CYP3A4 and thus interfere with the pharmacokinetics of many other drugs that are metabolised by this enzyme. In contrast, although closely related, azithromycin is not a cytochrome inhibitor. All quinolones form complexes with di- and trivalent cations and, therefore, the absorption of quinolones can be dramatically reduced when given concomitantly with mineral antacids, zinc or iron preparations. Ciprofloxacin exhibits an inhibitory potential for the cytochrome isoenzyme 1A2, resulting in an inhibition of theophylline metabolism. Other quinolones, such as levofloxacin or moxifloxacin, do not interfere with theophylline metabolism. The systemic azoles, such as ketoconazole, itraconazole, fluconazole and voriconazole, are inhibitors of CYP isoenzymes, such as CYP3A4, CYP2C9 and CYP2C19, to varying degrees. In addition, some are substrates of the MDR-1 gene product, P-glycoprotein. These features are the basis for most of the interactions occurring during azole therapy (e.g., in severely ill patients in the hospital who are treated with multiple drugs).     

A comparative study of 1-substituted imidazole and 1,2,4-triazole antifungal compounds as inhibitors of testosterone hydroxylations catalysed by mouse hepatic microsomal cytochromes P-450

Three imidazole antifungal agents, ketoconazole, miconazole and tioconazole, and a group of structurally related 1-substituted imidazole and 1,2,4-triazole compounds were evaluated as inhibitors of the oxidative metabolism of testosterone catalysed by mouse hepatic microsomal cytochromes P-450. Spectroscopic studies showed that both imidazoles and triazoles interacted with ferric cytochrome P-450 in hepatic microsomes to produce type II difference spectra which could be distinguished by their different absorbance maxima; 429-430 nm and 425-426 nm respectively. Compound 4, which possesses both types of functional group, produced a spectrum which resembled that of imidazole compounds, indicating that the imidazole moiety had a higher affinity than the triazole for the haem of cytochromes P-450 present in microsomes. The test compounds differentially inhibited regio- and stereo-specific testosterone metabolism and the pattern of inhibition varied with the 1-substituent on the azole ring. Ketoconazole was a potent inhibitor of testosterone 6 beta-hydroxylation (IC50 0.08 microM) but was considerably less active against other hydroxylations and 17 beta-oxidation to androstenedione (IC50 range 13 to greater than 100 microM). In contrast, tioconazole (IC50 range 0.18 to 3.3 microM) and miconazole (IC50 range 0.15 to 10 microM) were relatively non-selective. Compounds 1 and 2, which differed from each other only in the type of azole ring, were most active against 16 beta-hydroxylation. The triazole analogue (compound 2) was a significantly more potent inhibitor of 16 beta-hydroxylation than the imidazole (compound 1), equipotent against androstenedione formation and less active against the other hydroxylations. Two relatively polar bis-azole analogues (compounds 3 and 4) were most active against androstenedione formation; however, in general they were less inhibitory than the lipophilic azoles. We conclude that azole antifungal agents of differing structure show different patterns of selective interaction with cytochromes P-450, a phenomenon primarily dependent on the 1-substituent on the azole ring, but also modulated to a lesser extent by the type of azole ring (imidazole or triazole).     

Comparison of two azole antifungal drugs, ketoconazole, and fluconazole, as modifiers of rat hepatic monooxygenase activity

The mechanism of action of azole antifungal agents is believed to involve inhibition of fungal cytochrome P-450, and, therefore, an investigation of the interaction of these drugs with mammalian cytochrome P-450 systems should provide some indication of their selectivity as antifungal agents. The ability of ketoconazole and fluconazole, the latter representing a new generation of triazole antifungal agents, to modify rat mixed function oxidase activity has been investigated in vitro with hepatic microsomes and in vivo using a N-methyl-[14C] antipyrine breath test. As a measure of selectivity the results have been compared with antifungal potency. Ketoconazole is more potent than fluconazole by an order of magnitude in inhibiting metabolism by O-dealkylation of ethoxycoumarin, methoxycoumarin and ethoxyresorufin (IC50 values of 6, 5 and 130 microM for ketoconazole respectively). The effects on the regio- and stereospecific hydroxylation of [14C] testosterone were also measured; the IC50 values for inhibition of total testosterone metabolism were 0.1 mM and greater than 3 mM for ketoconazole and fluconazole respectively. Marked selectivity differences were observed for the two drugs as indicated by ketoconazole being a potent inhibitor of 7 alpha-hydroxylation of testosterone (IC50 20 microM) while fluconazole did not inhibit this activity at 3 mM. In vivo investigations using a range of doses confirmed their ranking for inhibitory potency; the ED50 values for maximum demethylation rate were 17 mumol/kg and greater than 60 mumol/kg for ketoconazole and fluconazole respectively. Thus fluconazole has a lower propensity to interact with rat hepatic cytochrome P-450 and can be considered a more selective antifungal agent as its in vivo antifungal potency is an order of magnitude greater than ketoconazole.     

MDR- and CYP3A4-Mediated Drug–Drug Interactions

P-glycoprotein (P-gp), multiple drug resistance associated proteins (MRPs), and cytochrome P450 3A4 together constitute a highly efficient barrier for many orally absorbed drugs. Multidrug regimens and corresponding drug–drug interactions are known to cause many adverse drug reactions and treatment failures. Available literature, clinical reports, and in vitro studies from our laboratory indicate that many drugs are substrates for both P-gp and CYP3A4. Our primary hypothesis is that transport and metabolism of protease inhibitors (PIs) and NNRTIs will be altered when administered in combination with azole antifungals, macrolide, fluroquinolone antibiotics, statins, cardiovascular agents, immune modulators, and recreational drugs [benzodiazepines, cocaine, lysergic acid dithylamide (LSD), marijuana, amphetamine (Meth), 3,4-methylenedioxymethamphetamine (MDMA), and opiates] due to efflux, and/or metabolism at cellular targets. Therefore, such drug combinations could be a reason for the unexpected and unexplainable therapeutic outcomes. A number of clinical reports on drug interaction between PIs and other classes (macrolide antibiotics, azole antifungals, cholesterol lowering statins, cardiovascular medicines, and immunomodulators) are discussed in this article. MDCKII-MDR1 was employed as an in vitro model to evaluate the effects of antiretrovirals, azole antifungals, macrolide, and fluroquinolone antibiotics on efflux transporters. Ketoconazole (50 μM) enhanced the intracellular concentration of ³H ritonavir. The inhibitory effects of ketoconazole and MK 571 on the efflux of ³H ritonavir were comparable. An additive effect was observed with simultaneous incorporation of ketoconazole and MK 571. Results of ³H ritonavir uptake studies were confirmed with transcellular transport studies. Several fluroquinolones were also evaluated on P-gp-mediated efflux of ³H cyclosporin and 14C erythromycin. These in vitro studies indicate that grepafloxacin, levofloxacin, and sparfloxacin are potent inhibitors of P-gp-mediated efflux of 14C erythromycin and ³H cyclosporin. Simultaneous administration of fluoroquinolones and macrolides could minimize the efflux and metabolism of both of the drugs. Effects of erythromycin and ketoconazole on carbamazepine metabolism were examined. Formation of 10,11-epoxy carbamazepine, a major CBZ metabolite, was significantly inhibited by these agents. Therefore, drug efflux proteins (P-gp, MRPs) and metabolizing enzyme (CYP450) are major factors in drug interactions. Overlapping substrate specificities of these proteins result in complex and sometimes perplexing pharmacokinetic profiles of multidrug regimens. Drug–drug interactions with PIs and other coadministered agents for human immunodeficiency virus (HIV) positive population have been discussed in light of efflux transporters and metabolizing enzymes. This article provides an insight into low and variable oral bioavailability and related complications leading to loss of therapeutic activity of MDR and CYP 450 substrates.     

Application of support vector machines to in silico prediction of cytochrome p450 enzyme substrates and inhibitors

Cytochrome P450 enzymes are responsible for phase I metabolism of the majority of drugs and xenobiotics. Identification of the substrates and inhibitors of these enzymes is important for the analysis of drug metabolism, prediction of drug-drug interactions and drug toxicity, and the design of drugs that modulate cytochrome P450 mediated metabolism. The substrates and inhibitors of these enzymes are structurally diverse. It is thus desirable to explore methods capable of predicting compounds of diverse structures without over-fitting. Support vector machine is an attractive method with these qualities, which has been employed for predicting the substrates and inhibitors of several cytochrome P450 isoenzymes as well as compounds of various other pharmacodynamic, pharmacokinetic, and toxicological properties. This article introduces the methodology, evaluates the performance, and discusses the underlying difficulties and future prospects of the application of support vector machines to in silico prediction of cytochrome P450 substrates and inhibitors.     

Itraconazole: pharmacology, clinical experience and future development

Itraconazole is an orally active, broad-spectrum, triazole antifungal agent which has a higher affinity for fungal cytochrome P-450 than ketoconazole but a low affinity for mammalian cytochrome P-450. Itraconazole has a broader spectrum of activity than other azole antifungals and shows interesting pharmacokinetic features in terms of its tissue distribution. These properties have resulted in reduced treatment times for a number of diseases such as vaginal candidiasis, as well as effective oral treatment of several deep mycoses, including aspergillosis and candidiasis. Currently itraconazole is registered in 42 countries for the treatment of systemic fungal infections. Further development is concentrating on antifungal prophylaxis as well as on an oral solution and an intravenous formulation.     

Update on natural product--drug interactions.

The interactions of natural products with drugs are discussed. Interactions between natural products and drugs are based on the same pharmacokinetic and pharmacodynamic principles as drug-drug interactions. Clinically important interactions appear to involve effects on drug metabolism via cytochrome P-450 isoenzymes, impairment of hepatic or renal function, and other possible mechanisms. Natural products that have been reported to interact with drugs in humans include coenzyme Q10, dong quai, ephedra, Ginkgo biloba, ginseng, glucosamine sulfate, ipriflavone, melatonin, and St. John's wort. In many cases, more research is needed to confirm these interactions and to determine whether other natural products may also interact with drugs. To effectively counsel patients about interactions involving natural products, pharmacists should be familiar with the most commonly used products and have access to information on more obscure products. In view of the less than stringent provisions of the Dietary Supplement Health and Education Act, pharmacists should consult reliable, independent sources of information on natural products rather than rely on literature provided by manufacturers. Pharmacists should recommend only those products that are manufactured to high quality-control standards. Natural products can interact with drugs and with other natural products by the same mechanisms as drugs.     

Interaction of azole antifungal agents with cytochrome P-45014DM purified from Saccharomyces cerevisiae microsomes

Mechanism of action of azole antifungal agents was studied by analyzing interaction of ketoconazole, itraconazole, triadimefon and triadimenol with a purified yeast cytochrome P-450 which catalyzes lanosterol 14 alpha-demethylation (P-45014DM). These antifungal agents formed low-spin complexes with P-45014DM, indicating the interaction of their azole nitrogens with the heme iron. Affinity of these antifungal agents for the cytochrome was extremely high compared with usual nitrogenous ligands. Upon reduction with sodium dithionite, the azole complexes of ferric P-45014DM were converted to the corresponding ferrous derivatives. Spectral analysis of these complexes suggested that geometric orientation of the azole moiety of an antifungal agent to the ferrous heme iron was regulated by the interaction between the N-1 substituent and the heme environment. CO could not readily replace ketoconazole or itraconazole co-ordinating to the heme iron of ferrous P-45014DM while triadimefon and triadimenol complexes of the cytochrome were promptly converted to the CO complexes. The inhibitory effects of ketoconazole and itraconazole on the P-45014DM-dependent lanosterol 14 alpha-demethylation were higher than that of triadimenfon. The substituents at N-1 of the azole moieties of ketoconazole and itraconazole are extremely large while those of triadimefon and triadimenol are relatively small. Accordingly, observations described above suggest that the N-1 substituent of an azole antifungal agent regulates the mobility of the molecule in the heme crevice of ferrous P-45014DM and determines the inhibitory effect of the compound.     

CYP3A4 and MDR Mediated Interactions in Drug Therapy

Multiple drug therapy is recommended in many disease states including AIDS, cancer, diabetes, and stroke. Therefore, drug-drug interactions can result in changes in pharmacological or toxicological response following concomitant administration of many therapeutic agents. It has become evident that two factors i.e. drug efflux pump- P-glycoprotein (MDR gene product) and metabolizing enzyme- CYP3A4 play major roles in this process. These two key proteins regulate all pharmacokinetic and pharmacodynamic interactions through the process of drug absorption, metabolism, disposition and elimination. Co-administration of two or more drugs can affect these processes due to altered functions of P-glycoprotein (P-gp) and CYP3A4 and consequently change clinical response and final outcome. After co-administration, some drugs may induce the activity of P-gp and/or CYP3A4 resulting in subtherapeutic blood levels and therapeutic failure due to reduced absorption and/or increased metabolism. Conversely, inhibition(s) of P-gp and/or CYP3A4 can cause enhanced plasma concentration and therefore, drug toxicity. Overlapping substrate specificities to these proteins make it difficult to understand perplexing pharmacokinetic interactions with multidrug regimens. Inter-patient variability of drug response can occur due to change in genetic profiles, intake of food, herbal supplement, and recreational drugs. In this review, we have outlined several clinically important CYP and MDR-mediated drug-drug interactions of antiretroviral agents, antineoplastic agents, azole antifungals, statins, methadone, antibacterials, cardiovascular medicines, immune modulators, recreational drugs and herbal agents. Mechanisms by which such drug interactions occur have been briefly discussed in some of the examples.     

Antifungal agents. 11. N-substituted derivatives of 1-[(aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole: synthesis, anti-Candida activity, and QSAR studies

1-[(Aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazoles were recently reported by our group as potent anti-Candida agents belonging to the antifungal azole class. In the present paper the synthesis, anti-Candida activities, and QSAR studies on a novel series of N-substituted 1-[(aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1H-imidazole derivatives are reported. The newly synthesized azoles were tested against 12 strains of Candida albicans together with bifonazole, miconazole, itraconazole, fluconazole, and compounds 1a, 1b, 3a, 3b, and 3c used as reference drugs. In general, tested derivatives showed good antifungal activities, and the most potent compound was 1d (MIC(90) = 0.032 microg/mL), which was from 4- to 250-fold more potent than reference drugs. Catalyst software was applied to develop a quantitative pharmacophore model to be used for the rational design of new antifungal azoles. Some key interactions, as well as excluded volumes, further to the coordination bond of azole antifungals with the demethylase enzyme, are highlighted.