Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor

Artemisinin drugs are of utmost importance in the treatment of malaria, because they represent the sole class of therapeutically used antimalarial drugs to which malaria parasites have not yet developed resistance. The major disadvantage of these medicines is the comparatively high recrudescence rate, which has been attributed to the remarkable decrease of artemisinin plasma concentrations during multiple dosing. Autoinduction of CYP2B6-mediated metabolism has been implicated as the underlying mechanism. So far, the molecular mechanism of induction by artemisinin has not been resolved. Because the xenosensors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) have been shown to mediate induction of drug-metabolizing enzymes and drug transporters, we investigated the hypothesis that artemisinin induces cytochrome P450 expression by activating PXR and/or CAR. By combining in vitro transfection methods and quantitative analyses of gene expression in cell lines and primary human hepatocytes, we here show that artemisinin drugs activate human PXR as well as human and mouse CAR and induce the expression of CYP2B6, CYP3A4, and MDR1 in primary human hepatocytes and in the human intestinal cell line LS174T. Furthermore, we demonstrate that artemisinin acts as a ligand of both nuclear receptors, because it modulates the interaction of the receptors with coregulators. In conclusion, activation of PXR and CAR and especially the resulting induction of CYP3A4 and MDR1 demonstrate that artemisinin has a higher risk of potential drug interactions than anticipated previously.     

Differential effects of clinically used derivatives and metabolites of artemisinin in the activation of constitutive androstane receptor isoforms

BACKGROUND AND PURPOSE Widespread resistance to antimalarial drugs requires combination therapies with increasing risk of pharmacokinetic drug-drug interactions. Here, we explore the capacity of antimalarial drugs to induce drug metabolism via activation of constitutive androstane receptors (CAR) by ligand binding. EXPERIMENTAL APPROACH A total of 21 selected antimalarials and 11 major metabolites were screened for binding to CAR isoforms using cellular and in vitro CAR-coactivator interaction assays, combined with in silico molecular docking. Identified ligands were further characterized by cell-based assays and primary human hepatocytes were used to elucidate induction of gene expression. KEY RESULTS Only two artemisinin derivatives arteether and artemether, the metabolite deoxyartemisinin and artemisinin itself demonstrated agonist binding to the major isoforms CAR1 and CAR3, while arteether and artemether were also inverse agonists of CAR2. Dihydroartemisinin and artesunate acted as weak inverse agonists of CAR1. While arteether showed the highest activities in vitro, it was less active than artemisinin in inducing hepatic CYP3A4 gene expression in hepatocytes. CONCLUSIONS AND IMPLICATIONS Artemisinin derivatives and metabolites differentially affect the activities of CAR isoforms and of the pregnane X receptor (PXR). This negates a common effect of these drugs on CAR/PXR-dependent induction of drug metabolism and further provides an explanation for artemisinin consistently inducing cytochrome P450 genes in vivo, whereas arteether and artemether do not. All these drugs are metabolized very rapidly, but only artemisinin is converted to an enzyme-inducing metabolite. For better understanding of pharmacokinetic drug-drug interaction possibilities, the inducing properties of artemisinin metabolites should be considered.     

In vitro interactions between antiretroviral protease inhibitors and artemisinin endoperoxides against Plasmodium falciparum

Antiretroviral protease inhibitors (APIs), which are effective at controlling the effects of human immunodeficiency virus (HIV) in patients, have also proven efficacious in inhibiting Plasmodium falciparum growth in vitro. Use of artemisinin-based combination therapies is being encouraged to reduce malaria mortality in areas of P. falciparum resistance to conventional antimalarial drugs. The aim of this study was to investigate drug interactions between HIV protease inhibitors and artemisinin drugs against malaria. In vitro cultures of P. falciparum provide a screen system for identifying and evaluating drug combinations. The derived isobolograms provide clear evidence of antagonistic interactions between artemisinin endoperoxides and several different APIs.     

青蒿素及其衍生物的研究进展

青蒿素类化合物是含过氧桥的化合物,在治疗多药抗药性恶性疟疾方面卓有成效。除此之外,该类化合物还具有抗肿瘤、抗真菌、抗心律失常、抗寄生虫等活性。本文就近年来国内外学者对青蒿素及其衍生物的结构改造及生物活性等方面的研究进行概述。     

Drug interactions of clinical importance with antihyperglycaemic agents: an update.

Because management of type 2 diabetes mellitus usually involves combined pharmacological therapy to obtain adequate glucose control and treatment of concurrent pathologies (especially dyslipidaemia and arterial hypertension), drug-drug interactions must be carefully considered with antihyperglycaemic drugs. Additive glucose-lowering effects have been extensively reported when combining sulphonylureas (or the new insulin secretagogues, meglitinide derivatives, i.e. nateglinide and repaglinide) with metformin, sulphonylureas (or meglitinide derivatives) with thiazolidinediones (also called glitazones) and the biguanide compound metformin with thiazolidinediones. Interest in combining alpha-glucosidase inhibitors with either sulphonylureas (or meglitinide derivatives), metformin or thiazolidinediones has also been demonstrated. These combinations result in lower glycosylated haemoglobin (HbA(1c)), fasting glucose and postprandial glucose levels than with either monotherapy. Even if modest pharmacokinetic interferences have been reported with some combinations, they do not appear to have important clinical consequences. No significant adverse effects, except a higher risk of hypoglycaemic episodes that may be attributed to better glycaemic control, occur with any combination. Challenging the classical dual therapy with sulphonylurea plus metformin, there is a recent trend to use alternative dual combinations (sulphonylurea plus thiazolidinedione or metformin plus thiazolidinedione). In addition, triple therapy with the addition of a thiazolidinedione to the metformin-sulphonylurea combination has been recently evaluated and allows glucose targets to be reached before insulin therapy is considered. This triple therapy appears to be safe, with no deleterious drug-drug interactions being reported so far.Potential interferences may also occur between glucose-lowering agents and other drugs, and such drug-drug interactions may have important clinical implications. Relevant pharmacological agents are those that are widely coadministered in diabetic patients (e.g. lipid-lowering agents, antihypertensive agents); those that have a narrow efficacy/toxicity ratio (e.g. digoxin, warfarin); or those that are known to induce (rifampicin [rifampin]) or inhibit (fluconazole) the cytochrome P450 (CYP) system. Metformin is currently a key compound in the pharmacological management of type 2 diabetes, used either alone or in combination with other antihyperglycaemics. There are no clinically relevant metabolic interactions with metformin, because this compound is not metabolised and does not inhibit the metabolism of other drugs. In contrast, sulphonylureas, meglitinide derivatives and thiazolidinediones are extensively metabolised in the liver via the CYP system and thus, may be subject to drug-drug metabolic interactions. Many HMG-CoA reductase inhibitors (statins) are also metabolised via the CYP system. Even if modest pharmacokinetic interactions may occur, it is not clear whether drug-drug interactions between oral antihyperglycaemic agents and statins may have clinical consequences regarding both efficacy and safety. In contrast, a marked pharmacokinetic interference has been reported between gemfibrozil and repaglinide and, to a lesser extent, between gemfibrozil and rosiglitazone. This leads to a drastic increase in plasma concentrations of each antihyperglycaemic agent when they are coadministered with the fibric acid derivative, and an increased risk of adverse effects.Some antihypertensive agents may favour hypoglycaemic episodes when co-prescribed with sulphonylureas or meglitinide derivatives, especially ACE inhibitors, but this effect seems to result from a pharmacodynamic drug-drug interaction rather than from a pharmacokinetic drug-drug interaction. No, or only modest, interferences have been described with glucose-lowering agents and other pharmacological compounds such as digoxin or warfarin. The effects of inducers or inhibitors of CYP isoenzymes on the metabolism and pharmacokinetics of the glucose-lowering agents of each pharmacological class has been tested. Significantly increased (with CYP inhibitors) or decreased (with CYP inducers) plasma levels of sulphonylureas, meglitinide derivatives and thiazolidinediones have been reported in healthy volunteers, and these pharmacokinetic changes may lead to enhanced or reduced glucose-lowering action, and thus hypoglycaemia or worsening of metabolic control, respectively. In addition, some case reports have evidenced potential drug-drug interactions with various antihyperglycaemic agents that are usually associated with a higher risk of hypoglycaemia.     

CYP-mediated clozapine interactions: how predictable are they?

Despite the introduction of newer drugs, the atypical antipsychotic clozapine remains the most effective drug in psychotic patients who are resistant to treatment with conventional agents. Optimal therapeutic responses to clozapine have been reported with serum concentrations between 350 microg/L and 1000 microg/L. Clozapine is frequently combined with other drugs to enhance efficacy and reduce adverse reactions but pharmacokinetic interactions can have a significant impact on drug response. The majority of the interactions with clozapine are reported to be mediated by cytochrome P450 (CYP) enzymes. CYP1A2 has a major role in the oxidative metabolism of clozapine, with a minor contribution from CYP3A4, and possibly CYP2D6, CYP2C9 and CYP2C19. Interactions mediated by potent CYP1A2 inhibitors (such as fluvoxamine) or inducers (like cigarette smoke) appear to be consistent, predictable and usually clinically significant. There are many case reports of interactions between clozapine and weak CYP1A2 inhibitors or inducers which are also potent inhibitors or inducers of CYP3A4 or CYP2D6. Researchers often explain these observations on the basis of the CYP1A2 involvement. In addition, there are case reports of clinically significant interactions between clozapine and drugs that are not substrates, inhibitors or inducers of CYP1A2. These interactions are difficult to predict and may not be consistent, as reflected by the conflicting literature reports. Further research to elucidate individual differences in clozapine metabolism, with the potential to detect the dominant roles of CYPs other than CYP1A2, may assist us in predicting these interactions.     

Evaluation of p450 inhibition and induction by artemisinin antimalarials in human liver microsomes and primary human hepatocytes

Artemisinin drugs have become the first-line antimalarials in areas of multidrug resistance. However, monotherapy with artemisinin drugs results in comparatively high recrudescence rates. Autoinduction of cytochrome P450 (P450)-mediated metabolism, resulting in reduced exposure, has been supposed to be the underlying mechanism. To better understand the autoinduction and metabolic drug-drug interactions (DDIs), we evaluated the P450s (particularly CYP2B6 and CYP3A4) inhibited or induced by two artemisinin drugs, Qing-hao-su (QHS) and dihydroartemisinin (DHA) using human liver microsome, recombinant P450 enzymes, and primary human hepatocytes. The results suggested that QHS was a weak reversible inhibitor of CYP2B6 (K(i) 4.6 μM), but not CYP3A4 (IC(50) ～ 50 μM) and did not show measurable time-dependent inhibition of either CYP2B6 or CYP3A4. DHA inhibited neither CYP2B6 nor CYP3A4 (IC(50) > 125 μM). In addition, it was found that QHS induced the activity of CYP3A4 (E(max) 3.5-fold and EC(50) 5.9 μM) and CYP2B6 (E(max) 1.9-fold and EC(50) 0.6 μM). Of the other P450s, UDP glucuronosyltransferases, and transporters studied, QHS and DHA had no significant effect except for minor induction of mRNA expression of CYP1A2 (E(max) 7.9-fold and EC(50) 5.2 μM) and CYP2A6 (E(max) 11.7-fold and EC(50) 4.0 μM) by QHS. Quantitative prediction of P450-mediated DDIs indicate autoinduction of QHS clearance with the AUC(i)/AUC ratio decreasing to 59%, as a result of a 1.9-fold increase in CYP3A4 and a 1.6-fold increase in CYP2B6 activity. These data suggest that QHS drugs are potential inducers of P450 enzymes, and the possible drug interactions (or lack thereof) with artemisinin drugs may be clinically relevant.     

Preventing antimalarial drug resistance through combinations.

Throughout the tropical world antimalarial drug resistance is increasing, particularly in the potentially lethal malaria parasite Plasmodium falciparum. In some parts of Southeast Asia, parasites which are resistant to chloroquine, pyrimethamine-sulfadoxine, and mefloquine are prevalent. The characteristics of a drug that make it vulnerable to the development of resistance are a long terminal elimination half-life, a shallow concentration-effect relationship, and that one or two base-pair mutations confer a marked reduction in susceptibility. The development of resistance can be delayed or prevented by drug combinations. The artemisinin derivatives are the most potent of all antimalarial drugs. They reduce the infecting parasite biomass by approximately 10 000-fold per asexual life cycle. There are good arguments for combining, de novo, an artemisinin derivative with all newly introduced antimalarial drugs.     

Clinically significant drug interactions with antidepressants in the elderly

Pharmacological treatment of depression in old age is associated with an increased risk of adverse pharmacokinetic and pharmacodynamic drug interactions. Elderly patients may have multiple disease states and, therefore, may require a variety of other drugs. In addition to polypharmacy, other factors such as age-related physiological changes, diseases, genetic constitution and diet may alter drug response and, therefore, predispose elderly patients to adverse effects and drug interactions. Antidepressant drugs currently available differ in their potential for drug interactions. In general, older compounds, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), have a higher potential for interactions than newer compounds, such as selective serotonin reuptake inhibitors (SSRIs) and other relatively novel agents with a more specific mechanism of action. In particular, TCAs and MAOIs are associated with clinically significant pharmacodynamic interactions with many medications frequently prescribed to elderly patients. Moreover, TCAs may be susceptible to pharmacokinetic interactions when given in combination with inhibitors or inducers of the cytochrome P450 (CYP) isoenzymes involved in their metabolism. Because of a more selective mechanism of action, newer antidepressants have a low potential for pharmacodynamic drug interactions. However, the possibility of the serotonin syndrome should be taken into account when drugs affecting serotonergic transmission, such as SSRIs, venlafaxine or nefazodone, are coadministered with other serotonergic agents. Newer agents have a differential potential for pharmacokinetic interactions because of their selective effects on CYP isoenzymes. Within the group of SSRIs, fluoxetine and paroxetine are potent inhibitors of CYP2D6, while fluvoxamine predominantly affects CYP1A2 and CYP2C19 activity. Therefore, these agents should be closely monitored or avoided in elderly patients treated with substrates of these isoforms, especially those with a narrow therapeutic index. On the other hand, citalopram and sertraline have a low inhibitory activity on different drug metabolising enzymes and appear particularly suitable in an elderly population. Among other newer antidepressants, nefazodone is a potent inhibitor of CYP3A4 and its combination with substrates of this isoform should be avoided.     

Current progress in the chemistry, medicinal chemistry and drug design of artemisinin based antimalarials

This review covers developments in relation to artemisinin-based antimalarial agents. Topics covered include a brief introduction to the history and treatment of malaria, and more recently, drug resistant malaria; the discovery of the naturally occurring novel peroxidic antimalarial artemisinin; artemisinin biosynthesis, metabolism and biotransformations; the diversity of proposed mechanisms of action; pharmacokinetics; the insight into structure-toxicity relationships; the total syntheses and the progress made in the syntheses of its analogs; and, ultimately the contribution of these efforts towards rational drug design in order to access potent, non-toxic antimalarial drugs based on artemisinin.     

The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions.

1. Little information is available about the pharmacokinetic interactions of anticancer drugs in man. However, clinically significant drug interactions do occur in cancer chemotherapy, and it is likely that important interactions have not been recognized. 2. Specific cytochrome P450 (CYP) enzymes have been recently shown to be involved in the metabolism of several essential anticancer agents. In particular, enzymes of the CYP3A subfamily play a role in the metabolism of many anticancer drugs, including epipodophyllotoxins, ifosphamide, tamoxifen, taxol and vinca alkaloids. CYP3A4 has been shown to catalyse the activation of the prodrug ifosphamide, raising the possibility that ifosphamide could be activated in tumour tissues containing this enzyme. 3. As examples of recently found, clinically significant interactions, cyclosporin considerably increases plasma doxorubicin and etoposide concentrations. Although cyclosporin and calcium channel blockers may influence the pharmacokinetics of certain anticancer agents by inhibiting their CYP3A mediated metabolism, it is more likely that these P-glycoprotein inhibitors inhibit P-glycoprotein mediated drug elimination. 4. Appropriate caution should be exercised when combining P-glycoprotein inhibitors and potential CYP3A inhibitors with cancer chemotherapy.     

Artemisinin Antimalarials: Preserving the "Magic Bullet"

The artemisinins are the most effective antimalarial drugs known. They possess a remarkably wide therapeutic index. These agents have been used in traditional Chinese herbal medicine for more than 2,000 years but were not subjected to scientific scrutiny until the 1970s. The first formal clinical trials of the artemisinins, and the development of methods for their industrial scale production, followed rapidly. A decade later, Chinese scientists shared their findings with the rest of the world; since then, a significant body of international trial evidence has confirmed these drugs to be far superior to any available alternatives. In particular, they have the ability to rapidly kill a broad range of asexual parasite stages at safe concentrations that are consistently achievable via standard dosing regimens. As their half-life is very short, there was also thought to be a low risk of resistance. These discoveries coincided with the appearance and spread of resistance to all the other major classes of antimalarials. As a result, the artemisinins now form an essential element of recommended first-line antimalarial treatment regimens worldwide. To minimize the risk of artemisinin resistance, they are recommended to be used to treat uncomplicated malaria in combination with other antimalarials as artemisinin combination therapies (ACTs). Their rollout has resulted in documented reductions in malaria prevalence in a number of African and Asian countries. Unfortunately, there are already worrisome early signs of artemisinin resistance appearing in western Cambodia. If this resistance were to spread, it would be disastrous for malaria control efforts worldwide. The enormous challenge for the international community is how to avert this catastrophe and preserve the effectiveness of this antimalarial "magic bullet". Drug Dev Res 71: 12-19, 2010. ? 2009 Wiley-Liss, Inc.     

Role of cytochrome P450 activity in the fate of anticancer agents and in drug resistance: focus on tamoxifen, paclitaxel and imatinib metabolism

Although activity of cytochrome P450 isoenzymes (CYPs) plays a major role in the fate of anticancer agents in patients, there are relatively few clinical studies that evaluate drug metabolism with therapeutic outcome. Nevertheless, many clinical reports in various non-oncology fields have shown the dramatic importance of CYP activity in therapeutic efficacy, safety and interindividual variability of drug pharmacokinetics. Moreover, variability of drug metabolism in the liver as well as in cancer cells must also be considered as a potential factor mediating cancer resistance.This review underlines the role of drug metabolism mediated by CYPs in pharmacokinetic variability, drug resistance and safety. As examples, biotransformation pathways of tamoxifen, paclitaxel and imatinib are reviewed.This review emphasises the key role of therapeutic drug monitoring as a complementary tool of investigation to in vitro data. For instance, pharmacokinetic data of anticancer agents have not often been published within subpopulations of patients who show ultra-rapid, extensive or poor metabolism (e.g. due to CYP2D6 and CYP2C19 genotypes).Besides kinetic variability in the systemic circulation, induction of CYP activity may participate in creating drug resistance by speeding up the cancer agent degradation specifically in the target cells. For one cancer agent, various mechanisms of resistance are usually identified within different cell clones. This review also tries to emphasise that drug resistance mediated by CYP activity in cancer cells should be taken into consideration to a greater degree.The unequivocal identification of the metabolising enzymes involved in clinical conditions will eventually allow improvement and individualisation of anticancer agent therapy, i.e. drug dosage and selection. In addition, a more complete understanding of the metabolism of anticancer agents will assist in the prediction of drug-drug interactions, as anticancer agent combinations are becoming more prevalent.     

Potentially significant drug interactions of class III antiarrhythmic drugs.

Class III antiarrhythmic drugs, especially amiodarone (a broad-spectrum antiarrhythmic agent), have gained popularity for use in clinical practice in recent years. Other class III antiarrhythmic drugs include bretylium, dofetilide, ibutilide and sotalol. These agents are effective for the management of various types of cardiac arrhythmias both atrial and ventricular in origin.Class III antiarrhythmic drugs may interact with other drugs by two major processes: pharmacodynamic and pharmacokinetic interactions. The pharmacodynamic interaction occurs when the pharmacological effects of the object drug are stimulated or inhibited by the precipitant drug. Pharmacokinetic interactions can result from the interference of drug absorption, metabolism and/or elimination of the object drug by the precipitant drug.Among the class III antiarrhythmic drugs, amiodarone has been reported to be involved in a significant number of drug interactions. It is mainly metabolised by cytochrome P450 (CYP)3A4 and it is a potent inhibitor of CYP1A2, 2C9, 2D6 and 3A4. In addition, amiodarone may interact with other drugs (such as digoxin) via the inhibition of the P-glycoprotein membrane transporter system, a recently described pharmacokinetic mechanism of drug interactions.Bretylium is not metabolised; it is excreted unchanged in the urine. Therefore the interactions between bretylium and other drugs (including other antiarrhythmic drugs) is primarily through the pharmacodynamic mechanism.Dofetilide is metabolised by CYP3A4 and excreted by the renal cation transport system. Drugs that inhibit CYP3A4 (such as erythromycin) and/or the renal transport system (such as triamterene) may interact with dofetilide.It appears that the potential for pharmacokinetic interactions between ibutilide and other drugs is low. This is because ibutilide is not metabolised by CYP3A4 or CYP2D6. However, ibutilide may significantly interact with other drugs by a pharmacodynamic mechanism.Sotalol is primarily excreted unchanged in the urine. The potential for drug interactions due to hepatic enzyme induction or inhibition appears to be less likely. However, a number of drugs (such as digoxin) have been reported to interact with sotalol pharmacodynamically.If concurrent use of a class III antiarrhythmic agent and another drug cannot be avoided or no published studies for that particular drug interaction are available, caution should be exercised and close monitoring of the patient should be performed in order to avoid or minimise the risks associated with a possible adverse drug interaction.     

Artemisia annua L.: a source of novel antimalarial drugs

Artemisia annua L. contains artemisinin, an endoperoxide sesquiterpene lactone, mainly in its leaves and inflorescences. This compound and a series of derivatives have attracted attention because of their potential value as antimalarial drugs. In this review a survey of the currently available literature data is given. It includes phytochemical aspects, such as constituents ofA. annua, the artemisinin content during the development of the plant and its biosynthesis, isolation, analysis and stability. Total chemical synthesis of artemisinin is referred to, as well as structure—activity relationships of derivatives and simplified analogues. Pharmacological studies are summarized, including the mechanism of action, interaction of the antimalarial activity with other drugs, possible occurrence of resistance to artemisinin, clinical results, toxicological aspects, metabolism and pharmacokinetics. Finally, plant cell biotechnologyy is mentioned as a possible means to obtain plants and cell cultures with higher artemisinin contents, allowing an industrial production of pharmaceuticals containing this novel drug.     

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.