Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new ketoconazole research articles will be listed here shortly after becoming available to us.
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Medical research on ketoconazole
Int J Pharm. 2008 May 14;
Ujie K, Oda M, Kobayashi M, Saitoh H
It has been shown that fexofenadine, a selective non-sedating histamine H(1)-receptor antagonist, is a substrate for P-glycoprotein (P-gp) and an organic anion transporting peptide (OATP). This study was undertaken to investigate the relative contribution of these absorptive and secretory transporters to the intestinal absorption of fexofenadine in rats. When 0.1mM fexofenadine was introduced into duodenal, jejunal, and ileal loops, its disappearance was around 10% over 30min. Cyclosporine A, but not ketoconazole, probenecid or mitoxantron, significantly increased fexofenadine disappearance in the ileal loops. The serosal-to-mucosal permeation of fexofenadine across the rat ileal segments was approximately 18-fold greater than its mucosal-to-serosal permeation. The secretory orientation of the ileal permeation of fexofenadine was weakened significantly in the presence of cyclosporine A, moderately in the presence of ketoconazole, but was unchanged in the presence of probenecid. When fexofenadine (0.1 or 0.5mM) was administered to rats intraluminally, plasma concentrations increased linearly up to 120min. The magnitude of the increase in plasma fexofenadine concentrations in the presence of cyclosporine A was more remarkable at 0.5mM than at 0.1mM. The results obtained in this study suggest that the intestinal absorption of fexofenadine is relatively small in rats even if OATP functions as an absorptive transporter for fexofenadine. Low absorption of fexofenadine in rats is attributed to potent secretory transport mediated by P-gp.
Planta Med. 2008 Jun 18;
Yoo HH, Lee SH, Jin C, Kim DH
The purpose of this investigation is to characterize the inhibition of CYP3A4 by methylenedioxyphenyl lignans isolated from ACANTHOPANAX CHIISANENSIS. Inhibition of CYP3A4 by three methylenedioxyphenyl lignans, avinin, helioxanthin, and 3-(3'',4''-dimethoxybenzyl)-2-(3',4'-methylenedioxybenzyl)butyrolactone was time-, concentration-, and NADPH-dependent and characterized by K(I) values of 2.4, 1.6, and 2.2 muM and K(inact) values of 0.030, 0.043, and 0.047 min (-1), respectively. The inhibition of CYP3A4 activity by these lignans was suppressed in the presence of a competitive CYP3A4 substrate, ketoconazole. Addition of nucleophiles or reactive oxygen scavenger and dialysis did not prevent inactivation of CYP3A4 by the ACANTHOPANAX lignans. The loss of CYP3A4 enzymatic activity resulting from incubation with the ACANTHOPANAX lignans was accompanied with a spectral loss of CYP3A4. These results collectively demonstrate that savinin, helioxanthin and 3-(3'',4''-dimethoxybenzyl)-2-(3',4'-methylenedioxybenzyl)butyrolactone from A. CHIISANENSIS inactivate CYP3A4 in a mechanism-based mode. CYP: cytochrome P450 CAP3A4: cytochrome P450 3A4 K (I): inhibitor concentration required for a half-maximal inactivation K (inact): maximal rate constant of the inactivation P450: cytochrome P450.
Blood monocyte derived Neo-Hepatocytes as in vitro test system for drug-metabolism.
Drug Metab Dispos. 2008 Jun 16;
Ehnert S, Nussler AK, Lehmann A, Dooley S
The gold standard for human drug metabolism studies is primary hepatocytes. However, availability is limited by donor organ scarcity. Therefore, efforts have been made to provide alternatives, e.g. the hepatocyte-like (NeoHep) cell type, which was generated from peripheral blood monocytes (PBMCs). In this study, expression and activity of phase I and phase II drug-metabolizing enzymes were investigated during trans-differentiation of NeoHep cells and compared to primary human hepatocytes. Important drug metabolizing enzymes are cytochrome P450 (CYP) iso-forms (1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4), microsomal epoxide hydrolase 1 (EPHX1), glutathione-S-transferase (GST) A1 and M1, N-acetyltransferase 1 (NAT1), NAD(P)H menadione oxidoreductase 1 (NMO1), Sulfotransferase 1A1 (SULT1A1) and UDP-glucoronosyltransferase 1A6 (UGT1A6). Monocytes and programmable cells of monocytic origin (PCMOs) expressed only a few of the investigated enzymes. Throughout differentiation, NeoHep cells showed a continuously increasing expression of all drug-metabolizing enzymes investigated, resulting in a stable basal activity after approximately 15 days. Fluorescence based activity assays indicated that NeoHep cells and primary hepatocytes have similar enzyme kinetics, although the basal activities were significantly lower in NeoHep cells. Stimulation with 3-Methylcholanthrene (3-MC) and Rifampicin (RIF) markedly increased CYP1A1/2 or CYP3A4 activities, which could be selectively inhibited by Nifedipine (NIF), Verapamil (VER), Ketoconazole (KET) and Quercetin (QUE). Our data reveal similarities in expression, activity, induction and inhibition of drug-metabolizing enzymes between NeoHep cells and primary human hepatocytes and hence suggest that NeoHep cells are useful as an alternative to human hepatocytes for measuring bio-activation of substances.
Risk Management of Simvastatin or Atorvastatin Interactions with CYP3A4 Inhibitors.
Drug Saf. 2008; 31(7): 587-96
Molden E, Skovlund E, Braathen P
BACKGROUND: Co-administration of cytochrome P450 (CYP) 3A4 inhibitors with simvastatin or atorvastatin is associated with increased risk of developing myopathy or rhabdomyolysis. OBJECTIVE: To detect co-prescriptions of CYP3A4 inhibitors with simvastatin or atorvastatin in community pharmacies and assess the risk-preventive actions taken by the prescribing physicians who were alerted about the co-prescription by the pharmacist. METHODS: This naturalistic study was performed during four separate 6-week periods in 2004 and 2005, and involved 110 Norwegian community pharmacists (25-30 in each period). Co-prescription of the selected CYP3A4 inhibitors diltiazem, verapamil, clarithromycin, erythromycin, fluconazole, itraconazole and ketoconazole with either simvastatin or atorvastatin was detected with the aid of a simple computer programme. In instances where the pharmacist alerted the prescribing physician about the co-prescription, information on possible strategies to minimize the risk associated with the interaction was also provided. Odds ratios (ORs) were estimated to describe the associations between prescription variables and frequencies of physician information and prescription change, respectively. RESULTS: In total, 245 co-prescriptions of CYP3A4 inhibitors with simvastatin (134 events) or atorvastatin (111) were detected. Diltiazem (86 events), verapamil (72), erythromycin (48) and clarithromycin (29) were the most commonly co-prescribed CYP3A4 inhibitors. Physicians were informed in 168 out of 245 cases (68.6%). The prescription was subsequently changed in 100 out of 168 cases (59.5%). Another 50 physicians (29.8%) responded that they would consult the patient and monitor potential adverse effects, while only 18 physicians (10.7%) replied that they had already managed the interactions or considered the issue as irrelevant. The adjusted OR for the informing of the physician was 1.89 (95% CI 0.98, 3.63) in patients receiving a daily HMG-CoA reductase inhibitor ('statin') dose of >/=40 mg compared with patients receiving a statin dose of
Drugs Today (Barc). 2008 May; 44(5): 369-80
Scheinfeld N
Topical ketoconazole, an imidazole, has been a mainstay of treatment for fungal infections and seborrheic dermatitis. Ketoconazole interferes with the fungal synthesis of ergosterol, a constituent of cell membranes, and has other antifungal effects. Shampoo, cream and oral formulations of ketoconazole have been available for many years. Recently, new foam and gel formulations of ketoconazole have been brought to market for the treatment of seborrheic dermatitis, which are effective against superficial fungal and yeast infections. The foam and gel formulations are likely to lead to a renascence of use of topical ketocona- zole for the treatment of skin disease, as patient preference and compliance might be augmented with such vehicles.
Antifungal Susceptibility for Common Pathogens of Fungal Keratitis in Shandong Province, China.
Am J Ophthalmol. 2008 Jun 9;
Xie L, Zhai H, Zhao J, Sun S, Shi W, Dong X
PURPOSE: To analyze common pathogens of fungal keratitis and results of antifungal drug sensitivity test in Shandong Province, China and provide guidance for appropriate choice of antifungal drugs in clinic. DESIGN: Retrospective, noncomparative study. METHODS: The pathogens isolated from 674 fungal keratitis patients between January 1, 2001 and December 31, 2006 were cultured and identified in Shandong Eye Institute, of which some common strains were tested for sensitivity to antifungal drugs. RESULTS: Fungi were positively cultured in 549 (81.5%) patients, in which the dominating pathogen was genus Fusarium (77.6%), with F. solani (37.3%), F. moniliforme (30.0%), and F. oxysporum (27.9%) being common species; Fusarium was mostly sensitive to natamycin, next to amphotericin B, and then to terbinafin. The second common pathogen was genus Aspergillus (10.8%), in which the main species were A. flavus (49.2%) and A. fumigatus (35.6%); Aspergillus was mostly sensitive to natamycin, next to terbinafin, and then to amphotericin B. Relatively, both Fusarium and Aspergillus were insensitive to ketoconazole, miconazole, itraconazole, fluconazole, and fluorocytosine. CONCLUSIONS: Fusarium is the most common pathogen of fungal keratitis, followed by Aspergillus, in Shandong Province, China. Natamycin is still the first choice in the treatment of hyphomycetic keratitis. Fusarium and Aspergillus are also sensitive to amphotericin B and terbinafin. Early diagnosis and treatments are vital to good prognosis in the treatment of fungal keratitis.
Adverse effects of ketoconazole in dogs - a retrospective study.
Vet Dermatol. 2008 Jun 11;
Mayer UK, Glos K, Schmid M, Power HT, Bettenay SV, Mueller RS
Although ketoconazole has been used extensively in dogs for the treatment of various fungal infections, information about adverse effects is mainly anecdotal. Common adverse effects in humans include dose-dependant anorexia, nausea and vomiting, allergic rashes and pruritus. Drug-induced hepatitis is very rare, but potentially fatal. The aim of this study was to evaluate the type and frequency of adverse effects associated with ketoconazole therapy in dogs treated for skin diseases and any possible influence of dosage, duration of therapy, signalment or concurrent medication. The medical records of 632 dogs treated with ketoconazole (2.6-33.4 mg/kg) were reviewed. Adverse effects occurred in 14.6% (92 dogs) and included vomiting (7.1%), anorexia (4.9%), lethargy (1.9%), diarrhea (1.1%), pruritus (0.6%), erythema (0.3%) and other adverse effects (2.5%). Of the dogs with other adverse effects, four of 16 (25%) were ataxic and three of these received concurrent ivermectin. Adverse effects were significantly more often recorded in dogs concurrently treated with ciclosporin (P = 0.034) or ivermectin (P = 0.007). Increased liver enzyme levels were reported rarely, and icterus was not seen in any of the dogs. However, monitoring liver enzymes during therapy is recommended, although this might not necessarily prevent severe idiosyncratic hepatotoxicity.
Rev Soc Bras Med Trop. 2008 Mar-Apr; 41(2): 158-62
Silva PR, Rabelo RA, Terra AP, Teixeira DN
This study identified Cryptococcus neoformans varieties isolated from 35 patients at teaching hospital of the Federal University of the Triângulo Mineiro and evaluated the susceptibility to antifungal agents among these samples using the protocol M27-A2 from the National Committee for Clinical Laboratory Standards. The gattii variety was identified in 11.4% of the cases (n = 4). The minimum inhibitory concentration (mg/ml) of Cryptococcus neoformans neoformans isolates ranged from 0.062 to 2.000 (amphotericin B), 0.250 to 8.000 (fluconazole), 0.062 to 1.000 (itraconazole) and 0.125 to 1.000 (ketoconazole). The gattii variety presented a minimum inhibitory concentration range of 0.125 to 2.000 (amphotericin B), 0.250 to 16.00 (fluconazole), 0.062 to 1.000 (itraconazole) and 0.125 to 4.000 (ketoconazole). Two isolates resistant to itraconazole and two resistant to amphotericin B (one isolate of each variety per antifungal agent) were found. These data show the importance of determining the variety and minimum inhibitory concentration of Cryptococcus neoformans isolates, in order to monitor resistance development and enable better treatment for cryptococcosis.
A Novel Bioactivation Pathway for Diclofenac Initiated by P450 Mediated Oxidative Decarboxylation.
Drug Metab Dispos. 2008 Jun 9;
Grillo MP, Ma J, Teffera Y, Waldon DJ
Diclofenac, a nonsteroidal antiinflammatory drug, undergoes bioactivation by cytochrome P450 oxidation to chemically-reactive metabolites that are capable of reacting with endogenous nucleophiles such as glutathione (GSH) and proteins and which may play a role in the idiosyncratic hepatotoxicity associated with the drug. Here, we investigated the ability of diclofenac to be metabolized to 2-(2,6-dichlorophenylamino)-benzyl-S-thioether glutathione (DPAB-SG) in incubations with rat (RLM) and human (HLM) liver microsomes fortified with NADPH and GSH. Thus, after incubation of diclofenac (50 microM) with liver microsomes (1 mg protein/mL), the presence of DPAB-SG was detected in both RLM and HLM incubation extracts by LC-MS/MS techniques. The formation of DPAB-SG was NADPH-, concentration- and time-dependent. Coincubation of diclofenac (10 microM) with ketoconazole (1 microM), an inhibitor of P450 3A4, with HLM led to a 75% decrease in DPAB-SG formation. However, by contrast, coincubation with the P450 2C9 inhibitor sulfaphenazole (10 microM) or the P450 2D6 inhibitor quinidine (40 microM) led to a 1.9 and 1.6 fold increase in DPAB-SG production, respectively. From these data, we propose that P450 3A4 mediates the oxidative decarboxylation of diclofenac resulting in the formation of a transient benzylic carbon-centered free radical intermediate which partitions between elimination (ortho-imine methide production) and recombination (alcohol formation) pathways. The benzyl alcohol intermediate, which was not analyzed for in the present studies, if formed could undergo dehydration to provide a reactive ortho-imine methide species. The ortho-imine methide intermediate then is proposed to react covalently with GSH forming DPAB-SG.
J Pharm Sci. 2008 Jun 6;
Ouyang H, Chen W, Andersen TE, Steffansen B, Borchardt RT
The objective of this study was to determine the relative importance of metabolism by cytochrome P450 (CYP) enzymes versus efflux by P-glycoprotein (P-gp) in restricting the intestinal mucosal permeation of cyclic prodrugs (AOA-DADLE, CA-DADLE, OMCA-DADLE) of the opioid peptide DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH). AOA-DADLE, CA-DADLE, and OMCA-DADLE were shown to be rapidly metabolized by rat liver microsomes and human CYP-3A4 and to a lesser extent by esterases. Using an in situ perfused rat ileum model, ketoconazole, a CYP 3A inhibitor, was shown to have no effect (AOA-DADLE) or a slight enhancing effect (OMCA-DADLE, twofold; CA-DADLE, threefold) on their intestinal mucosal permeation. In contrast, inclusion of PSC-833, a P-gp inhibitor, in the perfusate significantly enhanced (7-16-fold) the permeation of the three cyclic prodrugs. Since PSC-833 was found to be a weak inhibitor of CYP 3A4 and to have no inhibitory effects on esterases, phenol sulfotransferases, and glucuronyltransferases, it is suggested PSC-833 enhances intestinal mucosal permeation of these cyclic prodrugs by inhibiting their polarized efflux and not by inhibiting their metabolism. Furthermore, efflux transporters (e.g., P-gp), not metabolic enzymes (e.g., CYP 3A, esterases), restrict the permeation of peptide prodrugs across the rat intestinal mucosa. (c) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci.