Eletriptan metabolism by human hepatic CYP450 enzymes and transport by human P-glycoprotein.
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"Reaction phenotyping" studies were performed with eletriptan (ETT) to determine its propensity to interact with coadministered medications. Its ability to serve as a substrate for human P-glycoprotein (P-gp) was also investigated since a central mechanism of action has been proposed for this "triptan" class of drug. In studies with a characterized bank of human liver microsome preparations, a good correlation (r2 = 0.932) was obtained between formation of N-desmethyl eletriptan (DETT) and CYP3A4-catalyzed testosterone 6 beta-hydroxylation. DETT was selected to be monitored in our studies since it represents a significant ETT metabolite in humans, circulating at concentrations 10 to 20% of those observed for parent drug. ETT was metabolized to DETT by recombinant CYP2D6 (rCYP2D6) and rCYP3A4, and to a lesser extent by rCYP2C9 and rCYP2C19. The metabolism of ETT to DETT in human liver microsomes was markedly inhibited by troleandomycin, erythromycin, miconazole, and an inhibitory antibody to CYP3A4, but not by inhibitors of other major P450 enzymes. ETT had little inhibitory effect on any of the P450 enzymes investigated. ETT was determined to be a good substrate for human P-gp in vitro. In bidirectional transport studies across LLC-MDR1 and LLC-Mdr1a cell monolayers, ETT had a BA/AB transport ratio in the range 9 to 11. This finding had significance in vivo since brain exposure to ETT was reduced 40-fold in Mdr1a+/+ relative to Mdr1a-/- mice. ETT metabolism to DETT is therefore catalyzed primarily by CYP3A4, and plasma concentrations are expected to be increased when coadministered with inhibitors of CYP3A4 and P-gp activity. (+info)
Inhibition of voltage-gated Ca2+ entry into GH3 and chromaffin cells by imidazole antimycotics and other cytochrome P450 blockers.
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We have studied the effects of cytochrome P450 inhibitors on the entry of Ca2+ and Mn2+, used here as a Ca2+ surrogate for Ca2+ channels, in fura-2-loaded GH3 pituitary cells and bovine chromaffin cells depolarized with high-K+ solutions. Imidazole antimycotics were potent inhibitors (econazole greater than miconazole greater than clotrimazole greater than ketoconazole). alpha-Naphtoflavone and isosafrole, but not metyrapone, also inhibited the entry of Ca2+ and Mn2+ induced by depolarization. This inhibitory profile most resembles that reported for IA-type cytochrome P450. However, carbon monoxide (CO), a well-known cytochrome P450 antagonist, had no effect on Ca2+ (Mn2+) entry. Given the high selectivity of the imidazole antimycotics for the heme moiety, our results suggest that a hemoprotein closely related to cytochrome P450 (but insensitive to CO) might be involved in the regulation of voltage-gated Ca2+ channels. The inhibitory pattern was also similar to that previously reported for agonist-induced Ca2+ (Mn2+) influx in neutrophils and platelets, although CO was an efficient inhibitor in this case. These results pose the question of whether similarities in the sensitivity to cytochrome P450 inhibitors exhibited by receptor-operated and voltage-gated channels reflect unknown similarities either in structural features or regulation mechanisms. (+info)
Treatment failure in a case of fungal keratitis caused by Pseudallescheria boydii.
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A case is presented of Pseudallescheria boydii fungal keratitis in an agricultural welder. Treatment with azole antifungal drugs (miconazole and itraconazole) and with penetrating keratoplasty was unsuccessful in eradicating the infection, and eventually the eye was eviscerated. (+info)
Effects of imidazole derivatives on cytochromes P450 from human hepatocytes in primary culture.
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The expression of several forms of cytochrome P450 including P450 1A2, 2D6, 2E1, and 3A was investigated in human hepatocytes maintained in primary culture for 96 h in the absence or presence of 50 microM of various imidazole derivatives. These included ketoconazole, clotrimazole, miconazole, fluconazole, secnidazole and metronidazole. In addition, the typical inducers rifampicin and beta-naphthoflavone were used for comparison. Western and Northern blot analysis of microsomes and RNA prepared from these cultures as well as de novo synthesis experiments revealed that, among the imidazole derivatives tested, only clotrimazole was a strong rifampicin-like inducer of P450 3A. The expression of the other forms of P450 tested was not affected by the treatments. Analysis of the inhibition of 13 monoxygenase activities, including ethoxyresorufin and phenacetin O-deethylases, coumarin 7 alpha-, lauric acid 11- and 12-, mephenytoin 4-, debrisoquin 4-, and aniline hydroxylases, benzphetamine, aminopyrine, mephenytoin and erythromycin demethylases, and cyclosporin oxidase (representative of 10 different forms of P450 in human liver microsomes) revealed that ketoconazole was a strong and selective in vitro inhibitor of P450 3A (cyclosporin oxidase) with a Ki less than 1 microM. Clotrimazole and miconazole were also strong inhibitors of P450 3A-mediated activities in contrast to the other imidazole derivatives. (+info)
Liposomes targeted to deliver antisecretory agents to jejunal mucosa.
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The B subunit of cholera toxin has been covalently attached to the surface of liposomes made from a mixture of phosphatidylethanolamine, phosphatidylcholine and cholesterol. Adenylate cyclase inhibitors and chloride conductance inhibitors were encapsulated within the liposomes. These "targeted" liposomes were used to study the combined effects of this novel delivery system, and a limited number of possible antisecretory agents, on net fluid flux into the pig jejunum. A state of net secretory fluid flux was induced in isolated jejunal loops in weanling pigs by adding theophylline or cholera toxin to the lumen of the isolated loops. There was no reduction in net fluid secretion when liposome suspensions without encapsulated secretory inhibitors were added to fluid in the lumen of loops treated with theophylline. There was also no reduction in net fluid secretion when miconazole, alpha-phenylcinnamate or 5 nitro-2-(3-phenethylamino)benzoate were encapsulated within targeted liposomes added to isolated jejunal loops. The net fluid flux induced by exposure of jejunal loops to theophylline was significantly reduced by adding targeted liposomes containing 2'-deoxy-3'-AMP. The reduction involved a reversal of net secretory fluid flux to an absorptive value. The net fluid secretory response to treatment of loops with cholera toxin was also inhibited by treating loops with targeted liposomes containing 2'-deoxy-3'-AMP. However, the reversal of secretion was less complete for secretion induced by cholera toxin than for secretion induced by theophylline. The reduced antisecretory efficacy versus cholera toxin was not improved by encapsulating higher concentrations of 2'-deoxy-3'-AMP.(ABSTRACT TRUNCATED AT 250 WORDS) (+info)
In vitro activities of the new antifungal drug eberconazole and three other topical agents against 200 strains of dermatophytes.
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We have compared the in vitro activity of the new antifungal drug eberconazole with those of three other topical antifungal agents, clotrimazole, ketoconazole, and miconazole, against 200 strains of dermatophytes. MICs were determined by a microdilution method with optimal conditions determined in a previous study (an inoculum of 10(4) CFU/ml, an incubation temperature of 28 degrees C, an incubation period of 7 days, and a MIC endpoint of 100% inhibition of growth). In general, the four drugs tested showed low MICs. However, eberconazole was more active (P < 0.05) than the other three drugs against the majority of the species tested. Eberconazole represents an advantageous alternative for dermatophytoses where a topical therapy is required. (+info)
Estrogen elicits cytochrome P450--mediated flow-induced dilation of arterioles in NO deficiency: role of PI3K-Akt phosphorylation in genomic regulation.
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This study investigated the mechanisms responsible for the estrogen-dependent, cytochrome P450 (CYP)-mediated dilator responses to shear stress in arterioles of NO-deficient female rats and mice. Flow-induced dilation (FID) was assessed in isolated arterioles from N(G)-nitro-L-arginine methyl ester (L-NAME)-treated male and ovariectomized female rats before and after overnight incubation with 17beta-estradiol (17beta-E2, 10(-9) mol/L). In control conditions, prostaglandins (PGs) mediated FID, because indomethacin (INDO) abolished the responses. After incubation of the vessels with 17beta-E2, the basal tone of arterioles was significantly reduced and FID was augmented. INDO did not affect the dilation of the vessels incubated with 17beta-E2. Dilations of these vessels, however, were eliminated by PPOH and miconazole, inhibitors of CYP/epoxygenase. Simultaneous incubation of the vessels with 17beta-E2 plus ICI, 182,780, an estrogen receptor antagonist, or wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K) phosphorylation or the transcriptional inhibitor DRB, prevented the reduced arteriolar tone and the enhanced CYP-mediated FID caused by incubation of vessels with 17beta-E2. Western blot analysis indicated a significantly increased phospho-Akt level in arterioles incubated with 17beta-E2 compared with those without 17beta-E2. The enhanced phospho-Akt in response to 17beta-E2 was localized, by immunohistochemistry, to arteriolar endothelial cells. Moreover, GC-MS analysis indicated a significantly increased production of epoxyeicosatrienoic acids, vasodilator metabolites of CYP/epoxygenase, in arterioles incubated with 17beta-E2, a response that was prevented by ICI 182780 and wortmannin, respectively. Thus, estrogen, via a receptor-dependent, PI3K/Akt-mediated pathway, transcriptionally upregulates CYP activity, leading to an enhanced arteriolar response to shear stress. (+info)
Evaluation of an acetic acid ester of monoglyceride as a suppository base with unique properties.
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The objective of this investigation was to evaluate an acetic acid ester of monoglycerides made from edible, fully hydrogenated palm oil (AC-70) as a suppository base and compare it with a commercially available semisynthetic base (Suppocire AI). Benzocaine and miconazole were used as model drugs. Suppositories were prepared by the fusion method. The drug loads in the suppositories were kept at 2% to 5% (wt/wt). In vitro release of drug from the suppositories into Sorensen's phosphate buffer (pH 7.4) was studied using a US Pharmacopeia dissolution apparatus 1 and a spectrophotometer. The melting behavior of the bases and the physical state of the drug in the suppositories were studied using a differential scanning calorimeter (DSC). Powder x-ray diffractometry was used to study any possible polymorphic changes in the AC-70 base during formulation and storage. In vitro release studies revealed that the release of benzocaine from the AC-70 suppository was substantially slower than that of the commercial AI base. At a 2.5% (wt/wt) benzocaine load, the release of drug from the AC-70 suppositories was found to be linear. This slow and linear release was attributed to the physical property of the base, which forms liquid crystalline phases in the aqueous dissolution medium. The lyotropic liquid crystalline phase has the ability to incorporate drug into its structure and can control the release kinetics of the drug from such a system. The apparent pH of the release medium (water) was decreased by 1 to 1.5 pH units when the AC-70 base was used. The DSC studies revealed that the melting range of the AC-70 base is 36 degrees C to 38 degrees C, which is ideal for suppository formulations. The results of these studies support the possibility of using this new base for slow-release suppository formulations. This base may be of particular interest for a drug that requires an acidic environment to maintain its activity. (+info)