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At least 19 recordsLinked to original sources
PubMed2001

Clotrimazole binds to heme and enhances heme-dependent hemolysis: proposed antimalarial mechanism of clotrimazole.

Two recent studies have demonstrated that clotrimazole, a potent antifungal agent, inhibits the growth of chloroquine-resistant strains of the malaria parasite, Plasmodium falciparum, in vitro. We explored the mechanism of antimalarial activity of clotrimazole in relation to hemoglobin catabolism in the malaria parasite. Because free heme produced from hemoglobin catabolism is highly toxic to the malaria parasite, the parasite protects itself by polymerizing heme into insoluble nontoxic hemozoin or by decomposing heme coupled to reduced glutathione. We have shown that clotrimazole has a high binding affinity for heme in aqueous 40% dimethyl sulfoxide solution (association equilibrium constant: K(a) = 6.54 x 10(8) m(-2)). Even in water, clotrimazole formed a stable and soluble complex with heme and suppressed its aggregation. The results of optical absorption spectroscopy and electron spin resonance spectroscopy revealed that the heme-clotrimazole complex assumes a ferric low spin state (S = 1/2), having two nitrogenous ligands derived from the imidazole moieties of two clotrimazole molecules. Furthermore, we found that the formation of heme-clotrimazole complexes protects heme from degradation by reduced glutathione, and the complex damages the cell membrane more than free heme. The results described herein indicate that the antimalarial activity of clotrimazole might be due to a disturbance of hemoglobin catabolism in the malaria parasite.

Animals↗
PubMed2005

Clotrimazole inhibits hemoperoxidase of Plasmodium falciparum and induces oxidative stress. Proposed antimalarial mechanism of clotrimazole.

The mechanism of antimalarial activity of clotrimazole was studied placing emphasis on its role in inhibiting hemoperoxidase for inducing oxidative stress in Plasmodium falciparum. Clotrimazole, in the presence of H2O2, causes irreversible inactivation of the enzyme, and the inactivation follows pseudo-first order kinetics, consistent with a mechanism-based (suicide) mode. The pseudo-first order kinetic constants are ki = 2.85 microM, k(inact) = 0.9 min(-1), and t(1/2) = 0.77 min. The one-electron oxidation product of clotrimazole has been identified by EPR spectroscopy as the 5,5'-dimethyl-1-pyrroline N-oxide (DMPO) adduct of the nitrogen-centered radical (aN = 15 G), and as DMPO protects against inactivation, this radical is involved in the inactivation process. Binding studies indicate that the clotrimazole oxidation product interacts at the heme moiety, and the heme-clotrimazole adduct has been dissociated from the inactivated enzyme and identified (m/z 1363) by mass analysis. We found that the inhibition of hemoperoxidase increases the accumulation of H2O2 in P. falciparum and causes oxidative stress. Furthermore, the inhibition of hemoperoxidase correlates well with the inhibition of parasite growth. The results described herein indicate that the antimalarial activity of clotrimazole might be due to the inhibition of hemoperoxidase and subsequent development of oxidative stress in P. falciparum.

Animals↗
PubMed2004

Induction of cytochrome P4501A (CYP1A) by clotrimazole, a non-planar aromatic compound. Computational studies on structural features of clotrimazole and related imidazole derivatives.

The classical pathway for induction of cytochrome P4501A (CYP1A) by xenobiotics is ligand binding to the aryl hydrocarbon receptor (AhR). High-affinity AhR ligands are planar polyaromatic molecules such as the prototypic ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The present work investigated the ability of the imidazole derivative, clotrimazole [1-(2'chlorotrityl)imidazole, CLO], to induce CYP1A in cultured rainbow trout (Oncorhynchus mykiss) hepatocytes at the catalytic activity (determined as 7-ethoxyresorufin-O-deethylase, EROD) and at the transcriptional level. CLO resulted in a significant increase of hepatocyte EROD activity and CYP1A mRNA at a concentration of 1.56 microM. Computational studies on the molecular structure of CLO show that CLO is unlikely to take a planar conformation. Further indications that CLO does not behave like a planar AhR ligand come from the experimental observation that co-incubation of trout hepatocytes with CLO and the AhR antagonist, alpha-naphthoflavone (alpha-NF), did not result in an inhibition of CLO induction of CYP1A mRNA, whereas alpha-NF was able to inhibit CYP1A induction by the prototpyic, planar AhR ligand, beta-naphthoflavone. The experimental findings on CLO agree with previous results obtained for another non-planar imidazole derivative, 1-benzylimidazole (BIM). Further, computational studies showed that the non-planar imidazoles, BIM and CLO, are highly similar with respect to some electrostatic properties, namely the dipole moment and the molecular electrostatic potential (MEP). Overall our experimental and computational studies suggest that transcriptional activation of CYP1A by the imidazole derivatives CLO and BIM is mediated by a mechanism different to that of prototypic CYP1A inducers such as the planar AhR-ligands.

Animals↗
PubMed2005

Inhibition of tumor growth and prolonged survival of rats with intracranial gliomas following administration of clotrimazole.

OBJECT: Clotrimazole, an imidazole derivative and inhibitor of cytochrome P-450, inhibits the proliferation of cancer cells by downregulating the movement of intracellular Ca++ and K+ and by interfering with the translation initiation process. Clotrimazole inhibits the proliferation of human glioblastoma multiforme cells; it induces morphological changes toward differentiation and blocks the cell cycle in the G1/G1 phase. In vitro, clotrimazole enhances the antitumor effect of cisplatin by inducing wild-type p53-mediated apoptosis. The authors examined the effect of clotrimazole on tumor growth, sensitivity to cisplatin, and survival of rats with intracranial gliomas. METHODS: Cultured C6 and 9L glioma cells were exposed to clotrimazole, and cell growth was assessed using the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide colorimetric assay. Clotrimazole produced a dose- and time-dependent inhibition of cell proliferation. The growth inhibitory effect of clotrimazole could not be overcome by exogenous stimulation with epidermal growth factor. Both C6 and 9L glioma cells were implanted into the rat brain and after 5 days, the animals were treated with a daily single dose of clotrimazole for 8 consecutive days. Clotrimazole treatment caused a significant inhibition of intracranial tumor growth. The survival of rats with 9L gliomas was analyzed after 10 days of treatment with clotrimazole, cisplatin, or a combination of clotrimazole and cisplatin. Rats treated with either drug displayed a significantly prolonged survival time; however, the combination treatment resulted only in an additional survival benefit. CONCLUSIONS: Clotrimazole effectively inhibits cell proliferation and tumor growth, and prolongs survival of rats with intracranial gliomas. Clotrimazole may be considered a potential anticancer drug for treatment of intracranial gliomas.

Animals↗
PubMed2000

Novel effects of clotrimazole on Ca2+ signaling in Madin Darby canine kidney cells.

The effect of clotrimazole on Ca2+ signaling in Madin Darby canine kidney (MDCK) cells was investigated by using fura-2 as a Ca2+ indicator. Clotrimazole (1-30 microM) induced a concentration-dependent [Ca2+]i increase. The [Ca2+]i increase comprised an initial rise and a slow decay. External Ca2+ removal partly inhibited the Ca2+ signals by reducing both the initial rise and the decay phase, indicating that clotrimazole triggered both Ca2+ influx and Ca2+ release. Pretreatment with 30 microM clotrimazole in Ca2+-free medium abolished the Ca2+ release induced by thapsigargin (1 microM), an endoplasmic reticulum Ca2+ pump inhibitor, and conversely, pretreatment with thapsigargin prevented clotrimazole from releasing more Ca2+. This suggests that the thapsigargin-sensitive Ca2+ store is the source of clotrimazole-induced Ca2+ release. Clotrimazole (10 microM) triggered Mn2+ quench of fura-2 fluorescence which was partly inhibited by 1 mM La3+. Addition of 3 mM Ca2+ induced a [Ca2+]i increase after preincubation with 10 microM clotrimazole in Ca2+-free medium, indicating that clotrimazole activated capacitative Ca2+ entry. However, 10 and 30 microM clotrimazole inhibited 1 microM thapsigargin-induced capacitative Ca2+ entry by 21% and 74%, respectively. Pretreatment with 40 microM aristolochic acid to inhibit phospholipase A2 reduced 30 microM clotrimazole-induced Ca2+ release by 51%, but inhibiting phospholipase C with 2 microM U73122 had little effect. This implies that clotrimazole induces Ca2+ release in an IP3-independent manner, which could be modulated by phospholipase A2-coupled events.

Adenosine Triphosphate↗
PubMed2000

Emergence of resistance of Candida albicans to clotrimazole in human immunodeficiency virus-infected children: in vitro and clinical correlations.

Oropharyngeal candidiasis (OPC) is a common opportunistic infection in human immunodeficiency virus (HIV)-infected patients and other immunocompromised hosts. Clotrimazole troches are widely used in the treatment of mucosal candidiasis. However, little is known about the potential contribution of clotrimazole resistance to the development of refractory mucosal candidiasis. We therefore investigated the potential emergence of resistance to clotrimazole in a prospectively monitored HIV-infected pediatric population receiving this azole. Adapting the National Committee for Clinical Laboratory Standards M27-A reference method for broth antifungal susceptibility testing of yeasts to clotrimazole, we compared MICs in macrodilution and microdilution assays. We further analyzed the correlation between these in vitro findings and the clinical response to antifungal therapy. One isolate from each of 87 HIV-infected children was studied by the macrodilution and microdilution methods. Two inoculum sizes were tested by the macrodilution method (10(3) and 10(4) CFU/ml) in order to assess the effect of inoculum size on clotrimazole MICs. The same isolates also were tested using a noncolorimetric microdilution method. Clotrimazole concentrations ranged from 0.03 to 16 microg/ml. Readings were performed after incubation for 24 and 48 h at 35 degrees C. For 62 (71.2%) of 87 clinical isolates, the MICs were low (< or =0.06 microg/ml). The MIC for 90% of the strains tested was 0.5 microg/ml, and the highest MIC was 8 microg/ml. There was no significant difference between MICs at the two inoculum sizes. There was 89% agreement (+/-1 tube) between the microdilution method at 24 h and the macrodilution method at 48 h. If the MIC of clotrimazole for an isolate of C. albicans was > or =0.5 microg/ml, there was a significant risk (P < 0.001) of cross-resistance to other azoles: fluconazole, > or = 8 microg/ml (relative risk [RR] = 8.9); itraconazole, > or =1 microg/ml (RR = 10). Resistance to clotrimazole was highly associated with clinically overt failure of antifungal azole therapy. Six (40%) of 15 patients for whom the clotrimazole MIC was > or =0.5 microg/ml required amphotericin B for refractory mucosal candidiasis versus 4 (5.5%) of 72 for whom the MIC was <0.5 microg/ml (P = 0.001; 95% confidence interval = 2.3 to 22; RR = 7.2). These findings suggest that an interpretive breakpoint of 0.5 microg/ml may be useful in defining clotrimazole resistance in C. albicans. The clinical laboratory's ability to determine MICs of clotrimazole may help to distinguish microbiologic resistance from the other causes of refractory OPC, possibly reducing the usage of systemic antifungal agents. We conclude that resistance to clotrimazole develops in isolates of C. albicans from HIV-infected children, that cross-resistance to other azoles may develop concomitantly, and that this resistance correlates with refractory mucosal candidiasis.

AIDS-Related Opportunistic Infections↗
PubMed1997

Inhibition of intestinal Cl- secretion by clotrimazole: direct effect on basolateral membrane K+ channels.

We evaluated the effects of clotrimazole and clofibrate on Ca(2+)- and adenosine 3',5'-cyclic monophosphate (cAMP)-mediated Cl- secretion in the colonic cell line, T84. We used 1-ethyl-2-benzimidazolinone (1-EBIO) to activate the Ca(2+)-dependent K+ channel (KCa) in these cells to induce a sustained Cl- secretory current (Isc). Clotrimazole potently inhibited the KCa-dependent Isc, with an inhibition constant (Ki) of 0.27 +/- 0.02 microM. Clofibrate also inhibited the 1-EBIO-induced Isc albeit with lower affinity (Ki = 6.5 +/- 1.2 microM). Clotrimazole (10 microM) inhibited the Isc response to the Ca(2+)-mediated agonist, carbachol, by 82%. Similarly, both clotrimazole and clofibrate inhibited cAMP-mediated Cl- secretion, with Ki values of 5.2 +/- 1.0 and 6.7 +/- 1.1 microM, respectively. We used nystatin to permeabilize the apical or basolateral membrane to determine the effects of clotrimazole and clofibrate on the basolateral K+ (IK) and apical Cl- (ICl) currents following stimulation by either 1-EBIO or forskolin. Both clotrimazole and clofibrate inhibited the 1-EBIO- and forskolin-induced IK without affecting ICl. We determined the effects of clotrimazole and clofibrate on KCa using 86Rb+ uptake studies into membrane vesicles. Both clotrimazole and clofibrate inhibited the 1-EBIO-induced 86Rb+ uptake, with Ki values of 0.31 +/- 0.08 and 10.8 +/- 5.5 microM, respectively. Similarly, clotrimazole inhibited the Ca(2+)-induced 86Rb+ uptake with a Ki of 0.51 +/- 0.15 microM. Charybdotoxin inhibited both the 1-EBIO- and Ca(2+)-induced 86Rb+ uptakes with similar affinities (Ki values of 0.57 +/- 0.07 and 0.47 +/- 0.08 nM, respectively), suggesting 1-EBIO and Ca2+ activate the same channel (KCa) in this assay. In excised, single-channel recordings both clotrimazole and clofibrate inhibited KCa, demonstrating a direct inhibition of the channel by these compounds. We demonstrate that clotrimazole blocks the intestinal KCa, thereby inhibiting Cl- secretion. These results suggest that clotrimazole may be useful as an antidiarrheal.

Benzimidazoles↗
PubMed1999

Effects of clotrimazole on the growth, morphological characteristics, and cisplatin sensitivity of human glioblastoma cells in vitro.

OBJECT: Clotrimazole, an antimycotic drug, inhibits proliferation of normal and cancer cells by downregulating the movement of intracellular Ca++ and K+. The authors examined the effect of clotrimazole on the growth and sensitivity to cisplatin of two human glioblastoma cell lines--A172, which has the wild-type p53 gene, and T98G, which has the mutant p53 gene in vitro. METHODS: The A172 and T98G glioblastoma cells were exposed to clotrimazole and cell growth was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium chloride colorimetric assay. Clotrimazole produced a dose-dependent inhibition of cell proliferation and caused changes in cellular structure toward a well-differentiated form. The growth inhibitory effect of clotrimazole was reversible. Western immunoblot analysis revealed a marked increase in cellular glial fibrillary acidic protein and wild-type p53 and a decrease in c-myc and c-fos oncoproteins in both cell lines treated with clotrimazole. Flow cytometric analysis revealed that clotrimazole-treated cells accumulated in the G0/G1 phase with a marked decrease in cells in the S phase; when clotrimazole was washed out from the culture medium, cells again started to proliferate, with a marked decrease in cells in the G0/G1 phase and an increase in cells in the S phase. The growth inhibitory effect of clotrimazole could not be overcome by exogenous stimulation with either epidermal growth factor or c-myc peptide. A combined treatment with clotrimazole and cisplatin significantly enhanced cell cytotoxicity compared with treatment using either drug alone. A DNA fragmentation assay showed that both clotrimazole and cisplatin induced apoptosis, which was increased in cells treated by both drugs. CONCLUSIONS: The present study indicates that clotrimazole inhibits cell proliferation accompanied by morphological changes toward differentiation of glioblastoma cells and that this drug synergistically enhances the antitumor effect of cisplatin by inducing wild-type p53-mediated apoptosis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Clotrimazole, an inhibitor of epidermal benzo(a)pyrene metabolism and DNA binding and carcinogenicity of the hydrocarbon.

Clotrimazole, a topically applied imidazole antifungal agent widely used in dermatological practice, was shown to be a potent inhibitor of the epidermal metabolism of benzo(a)pyrene (BP) and its microsomal enzyme-mediated binding both to neonatal rat epidermal DNA in vivo and to calf thymus DNA in vitro. Varying concentrations of clotrimazole added to in vitro incubation systems resulted in a dose-dependent inhibition of cytochrome P-450-dependent microsomal aryl hydrocarbon hydroxylase (AHH) in control animals as well as in animals pretreated with topical application of known inducers of the enzyme. Inhibition of epidermal AHH by topically applied clotrimazole was time and dose dependent. The 50% inhibition of clotrimazole for epidermal AHH ranged from 0.12 to 0.25 microM, which suggests that clotrimazole is among the most potent inhibitors of epidermal AHH yet identified. Clotrimazole was also found to be a potent inhibitor of epoxide hydrolase activity in vitro with a 50% inhibition at 0.1 mM. High-pressure liquid chromatographic analysis of the metabolism of BP in rat epidermal microsomes revealed substantial inhibition of metabolite formation by clotrimazole. This occurred in microsomes prepared from untreated as well as animals pretreated with inducers of the enzyme. Furthermore, a single topical application of clotrimazole resulted in 80 and 30% induction of epidermal and hepatic glutathione S-transferase activity, respectively. Topical application of clotrimazole to the skin of BALB/c mice substantially increased the latent period for the development of skin tumors by 3-methylcholanthrene. These studies indicate that clotrimazole is an extremely potent inhibitor of epidermal BP metabolism and of the DNA-binding of polycyclic aromatic hydrocarbon (PAH) carcinogens, and is an enhancer of enzymes necessary for detoxification of the PAH. Clotrimazole also reduces the formation of carcinogenic and mutagenic metabolites of BP in vitro and in vivo and inhibits induction of skin tumors by the PAH. These data indicate that the imidazole antifungal clotrimazole offers promise as an agent useful for the modulation of PAH cancer risk in the skin.

Animals↗
PubMed1998

Clotrimazole, an imidazole antimycotic, is a potent inhibitor of angiogenesis.

Clotrimazole, an imidazole antimycotic, interferes with the rise in cytosolic Ca2+ and inhibits cell proliferation in a reversible manner. Here we describe the effect of clotrimazole on vascular endothelial cells (ECs). Clotrimazole inhibited the proliferation of ECs stimulated with typical angiogenic growth factors; vascular endothelial growth factor and basic fibroblast growth factor (bFGF). This inhibitory effect of clotrimazole was dose-dependent and the maximal inhibition was observed at a concentration of 10 mM. We did not observe any increase in 51Cr release from ECs during treatment with 10 microM clotrimazole. Moreover, clotrimazole inhibited the basal and bFGF-stimulated migration of ECs. As clotrimazole inhibited two principle components of angiogenesis; the proliferation and migration of ECs, we examined whether clotrimazole inhibited angiogenesis. Tube formation by ECs in type 1 collagen gel was investigated, and clotrimazole was found to be significantly inhibitory. The inhibitory effect of clotrimazole on angiogenesis was further confirmed in an in vivo angiogenesis model of murine Matrigel plug assay. These results demonstrate that clotrimazole is a potent inhibitor of angiogenesis.

Animals↗
PubMed1999

Inhibition of Ca2+-activated K+ current by clotrimazole in rat anterior pituitary GH3 cells.

The ionic mechanism of clotrimazole, an imidazole antimycotic P-450 inhibitor, was examined in rat anterior pituitary GH3 cells. In perforated-patch whole-cell recording experiments, clotrimazole reversibly caused an inhibition of the Ca2+-activated K+ current in a dose-dependent manner. The IC50 value of the clotrimazole-induced inhibition of I(K(Ca)) was 3 microM. In the outside-out configuration of single channel recording, application of clotrimazole (10 microM) into the bath medium did not change the single channel conductance of large conductance Ca2+-activated K+(BK(Ca)) channels, but it suppressed the channel activity significantly. The change in the kinetic behavior of BK(Ca) channels caused by clotrimazole in these cells is found to be due to a decrease in mean open time and an increase in mean closed time. Other structurally distinct P-450 inhibitors (e.g. ketoconazole or econazole) also effectively suppressed the amplitude of I(K(Ca)). Clotrimazole (10 microM) blocked both the inactivating and non-inactivating components of the voltage-dependent K+ outward current (I(K(V))), but it produced a slight reduction of L-type Ca2+ inward current (I(Ca,L)) without altering the current-voltage relationship of I(Ca,L). Clotrimazole (10 microM) also increased the firing rate of action potentials. These results provide direct evidence that clotrimazole is capable of suppressing the activity of BK(Ca) channel in GH3 cells. Because of the non-selective inhibitory effect of clotrimazole on I(K(Ca)) and I(K(V)), this inhibition is mainly, if not entirely, due to a direct channel blockade. Thus, the present study implies that the blockade of these ionic channels by clotrimazole would affect hormonal secretion and neuronal excitability.

Action Potentials↗
PubMed1997

Clotrimazole and efaroxan stimulate insulin secretion by different mechanisms in rat pancreatic islets.

It is now well established that the imidazoline insulin secretagogue efaroxan mediates its effects by inducing closure of ATP-sensitive potassium channels in the pancreatic beta-cell, leading to membrane depolarisation, Ca2+ influx and increased insulin secretion. However, a recent study has shown that efaroxan may also act as a blocker of a second class of potassium channel (the Kmaxi channel) in red blood cells, raising the possibility that its effects in islets could be mediated by interactions with both types of channel. Since the antimycotic imidazole compound clotrimazole is a highly potent blocker of Kmaxi channels, we have studied the effects of this drug on insulin secretion. Clotrimazole stimulated insulin secretion from rat islets of Langerhans incubated in the presence of 6 mM glucose, in a dose-dependent manner. Experiments performed at different glucose concentrations showed that the actions of clotrimazole were most prominent at low glucose concentrations whereas it did not enhance secretion beyond the rate induced by 20 mM glucose. The insulinotropic action of clotrimazole was temperature dependent but was independent of extracellular calcium. Clotrimazole appeared to block ATP-sensitive potassium channels in islets since, like efaroxan and glibencamide, it was able to prevent the inhibitory effects of diazoxide on glucose-induced insulin secretion. However, neither the direct stimulatory effect of clotrimazole on insulin release nor the abilty of clotrimazole to reverse the inhibitory actions of diazoxide was sensitive to blockade by the imidazoline secretagogue antagonist KU14R. Overall, the results suggest that clotrimazole exerts an insulinotropic effect in pancreatic beta-cells that is distinct from the actions of imidazoline secretagogues such as efaroxan. Clotrimazole can increase insulin secretion at sub-maximal glucose concentrations by an action which appears to be independent of membrane ion channel events.

Animals↗
PubMed2005

Concomitant clotrimazole therapy more than doubles the relative oral bioavailability of tacrolimus.

The purpose of this pharmacokinetic study was to determine whether the relative oral bioavailability of tacrolimus is increased with concomitant administration of clotrimazole. Pharmacokinetic studies were conducted in 6 adult kidney transplant patients receiving tacrolimus therapy. Pharmacokinetic profiling was performed by blood sampling over 12 hours before and after the administration of a 5-day course of clotrimazole. Tacrolimus whole-blood concentrations were determined by microparticle enzyme immunoassay. Noncompartmental pharmacokinetic analysis was conducted using WinNonLin, Standard Edition, Version 1.1. Concomitant administration of clotrimazole more than doubled the relative oral bioavailability of tacrolimus. The mean AUC0-12 of tacrolimus was increased 250% with clotrimazole (467.0 +/- 170.0 ng.h/mL versus 188.7 +/- 50.2 ng.h/mL; P = 0.002). Tacrolimus blood trough concentrations also more than doubled with coadministration of clotrimazole (27.7 +/- 10.4 ng/mL versus 11.6 +/- 4.0 ng/mL; P = 0.003). Mean Cmax was significantly increased with clotrimazole (70.7 +/- 34.7 ng/mL versus 27.4 +/- 11.1 ng/mL, P = 0.01). Tmax decreased from 3.2 +/- 1.6 hours to 1.9 +/- 1.0 hours (P = NS). In addition, the apparent oral clearance decreased 60% with coadministration of clotrimazole (median oral clearance 0.16 L/h/kg versus 0.40 L/h/kg; P = 0.03). Thus, clotrimazole causes a significant increase in the relative oral bioavailability, Tmax, and trough concentration of tacrolimus. Tacrolimus levels should be monitored following initiation or discontinuation of clotrimazole to minimize toxicity or precipitation of an acute rejection episode due to subtherapeutic levels.

Adult↗
PubMed2004

Enhancement of heme-induced membrane damage by the anti-malarial clotrimazole: the role of colloid-osmotic forces.

Two recent studies have demonstrated that clotrimazole, a well-known potential antifungal agent, inhibits the in vitro growth of chloroquine-resistant strains of the malaria parasite, Plasmodium falciparum. In a previous study, we suggested that clotrimazole acts as an anti-malarial agent by inhibiting heme catabolism in the malaria parasite and by enhancing heme-induced membrane damage. In this paper, we examined the mechanism of action by measuring hemolysis as an indicator of membrane damage. Our results showed that clotrimazole does not promote the binding of heme to membranes, and that the enhancement of heme-induced hemolysis by clotrimazole is not caused by lipid peroxidation or by oxidation of thiol groups in membrane proteins. Instead, clotrimazole inhibits glutathione-dependent heme degradation, resulting in an enhancement of heme-induced hemolysis. We also found that clotrimazole increases the susceptibility of erythrocytes to hypotonic lysis in the presence of heme and that sucrose could inhibit hemolysis induced by heme-clotrimazole complexes. Thus, it appears that the enhancement of heme-induced hemolysis by clotrimazole in our experiments is due to a colloid osmotic hemolysis mechanism. The hydrophobicity and the large molecular size of the heme-clotrimazole complex might be key factors for induction of hemolysis.

Animals↗
PubMed1989

Effect of topical application of clotrimazole to rats on epidermal and hepatic monooxygenase activities and cytochrome P-450.

Clotrimazole, an N-substituted imidazole, is a widely used topical agent for the treatment of superficial fungal infections. In this study, the effect of application of clotrimazole to the skin of neonatal rats on the induction response of the cytochrome P-450-dependent monooxygenase system in epidermis and liver has been examined. A single topical application of clotrimazole (10 mg/100 g) to rats resulted in a 53% increase in hepatic cytochrome P-450 content. Clotrimazole treatment also resulted in significant induction of epidermal 7-ethoxycoumarin-O-deethylase activity. Hepatic p-nitrophenol hydroxylase, an enzyme, catalyzed principally by the ethanol inducible cytochrome P-450 isozyme, was also significantly induced (58%) by topically applied clotrimazole. This enzyme activity was undetectable in epidermal microsomes. Further characterization of the cytochrome P-450 isozymes induced in liver by clotrimazole treatment was based on monoclonal antibodies (MAbs) raised against purified rat liver cytochrome P-450 isozymes induced by phenobarbital (MAb 2-66-3) and ethanol (MAb 1-98-1). Hepatic microsomes prepared from clotrimazole-treated rats showed significant immunoreactivity on Western blot with both the MAbs whereas no reactivity occurred in epidermal microsomes. Our data indicate that topical application of clotrimazole to rats results in the induction of selected cytochrome P-450 isozyme(s) in liver and epidermis which may have implications for the therapeutic use of this compound.

Administration, Topical↗
PubMed2006

Clotrimazole, an antifungal drug possessing diverse actions, increases the vulnerability to cadmium in lymphocytes dissociated from rat thymus.

Since clotrimazole, known as an antifungal drug, exerts diverse actions on cellular functions, it is expected that clotrimazole can be used for other purposes. This antifungal drug protects the cells overloaded with Ca(2+) by A23187, a calcium ionophore. Therefore, the agent may prevent the cells from death induced by heavy metals such as CdCl(2), PbCl(2), or HgCl(2) that are respectively proposed to increase intracellular Ca(2+) concentration. To test this possibility, we have examined the effect of clotrimazole on the cells simultaneously treated with CdCl(2), PbCl(2), or HgCl(2) using rat thymocytes and a flow cytometer with fluorescent probes. The simultaneous application of clotrimazole and CdCl(2) significantly decreased cell viability, even though the concentrations of both were ineffective at affecting the viability. The significant decrease in cell viability was not due to the inhibition of Ca(2+)-ATPase and Ca(2+)-dependent K(+) channels that were induced by clotrimazole. The simultaneous application increased the population of cells with phosphatidylserine exposed on membrane surface, indicating the change in asymmetrical distribution of membrane phospholipids. Furthermore, the cytotoxicity induced by the combination of clotrimazole and CdCl(2) under nominally Ca(2+)-free condition was more profound than that under normal Ca(2+) condition. Therefore, the membrane may be a target for the cytotoxic action of clotrimazole and CdCl(2) that were simultaneously applied. It is also the case for PbCl(2), but not the case for HgCl(2). It is concluded that clotrimazole can modulate the cytotoxicity of some heavy metals.

Animals↗
PubMed2001

Clotrimazole increases tacrolimus blood levels: a drug interaction in kidney transplant patients.

In order to substantiate a previous case report of a drug interaction between tacrolimus and clotrimazole, we randomly assigned tacrolimus-treated renal allograft recipients to therapy with either clotrimazole or nystatin for oral thrush prophylaxis immediately following transplantation. Patients receiving other agents known to interact with cytochrome P450 were excluded from the study. The clotrimazole group consisted of 17 patients and the nystatin group, which served as the control group, consisted of 18 patients. An oral loading dose (approximately 0.3 mg/kg) of tacrolimus was given pre-operatively. Post-transplant, tacrolimus (approximately 0.15 mg/kg) was orally administered twice daily. Clotrimazole therapy consisted of a 10-mg troche administered three times daily. Nystatin therapy consisted of the oral suspension (5 mL) administered as a 'swish and swallow' four times daily. We evaluated tacrolimus trough blood levels and tacrolimus doses on days 1, 3, 5, and 7 following transplantation. On post-transplant day 1, mean tacrolimus trough levels did not differ between clotrimazole- and nystatin-treated patients. Mean tacrolimus blood trough levels were significantly higher in clotrimazole-treated patients on days 3, 5, and 7 post-transplant, 42+/-14, 53+/-7, and 33+/-17 ng/mL, respectively, compared to 15+/-8, 15+/-7, and 14+/-6 ng/mL in nystatin-treated patients (p<0.05). The mean tacrolimus dose was significantly lower in the clotrimazole group by day 7 post-transplant (p<0.05). We conclude that clotrimazole therapy may cause a significant rise in tacrolimus trough blood levels. Recognition of this potential drug interaction is essential to minimize tacrolimus-associated toxicities in the early post-transplant period.

Adult↗