Induction potential of fluconazole toward drug-metabolizing enzymes in rats

Lavrijsen, Karel; Houdt, J. M. G. van; Dyck, Dirk M. J. Van; Meuldermans, W.; Heykants, J.

doi:10.1128/aac.34.3.402

Cited by 20 publications

(9 citation statements)

References 28 publications

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“…Animal data indicate that at a dose of 160 mg kg-l, fluconazole slightly decreases UGT activity [12]. However, this is a much higher dose than that used in clinical practice.…”

Section: Discussionmentioning

confidence: 92%

Comparative effects of antifungal agents on zidovudine glucuronidation by human liver microsomes.

Sampol¹,

Lacarelle²,

Rajaonarison³

et al. 1995

Brit J Clinical Pharma

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Zidovudine (ZDV) is extensively metabolised by the liver to an inactive glucuronide (GZDV). Since ZDV is often administered with antimycotic drugs, we studied the effect of six systemic antifungal agents on the in vitro glucuronidation of ZDV by human liver microsomes. 5-fluorocytosine and itraconazole had no inhibitory effect whereas amphotericine B, ketoconazole, miconazole and fluconazole inhibited in vitro GZDV formation (Ki values were 0.13, 0.08, 0.18 and 1.4 mm respectively).

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“…Animal data indicate that at a dose of 160 mg kg-l, fluconazole slightly decreases UGT activity [12]. However, this is a much higher dose than that used in clinical practice.…”

Section: Discussionmentioning

confidence: 92%

Comparative effects of antifungal agents on zidovudine glucuronidation by human liver microsomes.

Sampol¹,

Lacarelle²,

Rajaonarison³

et al. 1995

Brit J Clinical Pharma

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“…Fluconazole on the other hand behaved as a high magnitude inducer of cytochrome P-450 and of cytochrome P-450 dependent enzyme activities, in a dose-dependent way in mice ( Figure 11) as well as in rats (Figure 12). Even at 10 mg/kg/d a significant induction of several enzymatic activities was seen in both animal species (26).TheED,, of fluconazole to shorten the methohexital hypnosis time in rats by more than 50% was 22.6 mg/kg (2). These effects occurred already at plasma and liver concentrations of ffuconazole comparable to those obtained in man at therapeutic dose levels.…”

Section: Induction Potentialmentioning

confidence: 99%

“…This feature is unique for itraconazole since P-450 (2, 9,29). (26). other azole antifungals do have inducing potential at highdoselevels (e.g.…”

Section: Induction Potentialmentioning

confidence: 99%

The Clinical Pharmacokinetics of Itraconazole: An Overview

Heykants

Peer

Velde

et al. 1989

Mycoses

369

263

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Itraconazole (R 51211) is the prototype of a class of triazole antifungals characterized by a high lipophilicity. This property determines to a large extent the pharmacokinetics of itraconazole and differentiates it from the hydrophilic triazole antifungaI fl uconazole.The pharmacokinetics of itraconazole in man are characterized by a good oral absorption, an extensive tissue distribution with tissue concentrations many times higher than in plasma, a relatively long elimination half-life of about one day and a biotransformation into a large number of metabolites. One of them, hydroxy-itraconazole, is antifungally active and explains why antifungal plasma levels, when measured by bioassay, are about three times the itraconazole levels measured by a specific HPLC-method.Distribution studies have shown that therapeutically active levels of itraconazole are maintained much longer in some infected tissues than in plasma. For instance, active levels persist for four days in the vaginal epithelium after a one-day treatment and for 3 weeks in the stratum corneum of the skin after treatment has been stopped. Unlike fluconazole, itraconazole does not interfere with mammalian drug metabolizing enzymes, minimizing the risk of interaction with concomitantly administered drugs. These pharmacokinetic properties may contribute to the high eficacy and safety of itraconazole in patients with various mycotic infections. New pharmaceutical formulations are being explored in order to broaden the application field of itraconazole to intravenous and oral therapy of patients with malabsorption.

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“…The use of hepatocytes of both animal and human origin in an early stage of drug development for residue toxicity and kmetic studies, is highly recommended since (i) species specific biotransformation pathways may be identified, (ii) the appropriate animal species for toxicity testing may be selected, and (iii) metabolites may be identified as marker residues in residue studies. This has successfully been demonstrated in case of the anthelmintic levamisole [130]. The observed similarity between metabolic pathways of levamisole in hepatocytes from various animal species, and the agreement between in-vitro and in-vivo metabolism in cattle has led to a substantial reduction in animal experiments with radiolabeled material.…”

Section: Collection Of Respiratory Productsmentioning

confidence: 87%

Pesticides report 40: Bound xenobiotic in food commodities of plant and animal origin (Technical Report)

Skidmore¹,

Paulson²,

Kuiper³

et al. 1998

Pure and Applied Chemistry

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Republication or reproduction of this report or its storage and/or dissemination by electronic means is permitted without the need for formal IUPAC permission on condition that an acknowledgement, withfull reference to the source along with use of the copyright symbol 0, the name IUPAC and the year of publication are prominently visible. Publication of a translation into another language is subject to the additional condition of prior approval from the relevant IUPAC National Adhering Organization. 1423Unauthenticated Download Date | 5/11/18 5:51 PM 1424 COMMISSION ON AGROCHEMICALS AND THE ENVIRONMENTPesticides report: bound xenobiotic residues in food commodities of plant and animal origin Synopsis: In order to assess the dietary risk resulting from the use of pesticides or veterinary drugs the nature of the chemical residues on food commodities needs to be determined. Elucidation of the nature of the chemical residue is carried out using radiolabelled studies where the radiolabelled xenobiotic is applied or dosed in a manner which reflects use conditions. Food commodities are exhaustively extracted to remove the individual components of the residue. Once extracted the identity and toxicological significance of the components can be assessed and, where appropriate, analytical methods developed to quantitatively determine the amount of the components in food items.Depending on the characteristics of the components of the residue, the extraction regime may not remove all the chemical residue from the sample matrix. These residues are frequently characterised as being "bound", however the amount and nature of this residue will be highly dependant on the extraction regime used. To provide guidance and standardisation a definition of the term "bound residues" is recommended. This definition builds on a previous IUPAC definition but takes account of the current availability of enzyme systems which effectively solubilise the entire matrix rather than extracting the residue. It is also recommended that where the extraction falls short of the full definition then the residues should be termed as "unextractable" and the conditions of the extraction should also be defined .Where residues are bound the assessment of the dietary risk cannot be directly assessed thus raising issues relating to the significance of the bound residue. The overall toxicological significance of a bound residue will depend primarily on its bioavailability and the level of exposure. In order to determine the bioavailability, study design is crucial in order to perform a critical safety assessment. THE IUPAC COMMISSION ON AGROCHEMICALS AND THE ENVIRONMENT MAKES THE FOLLOWING RECOMMENDATIONS1) The revised definition for what constitutes a bound residue should be adopted.A xenobiotic bound residue is a residue which is associated with one or more classes of endogenous macromolecules. It cannot be dis-associated from the natural macro molecule using exhaustive extraction or digestion without significantly changing the nature of either the exocon or the...

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Induction potential of fluconazole toward drug-metabolizing enzymes in rats

Cited by 20 publications

References 28 publications

Comparative effects of antifungal agents on zidovudine glucuronidation by human liver microsomes.

Comparative effects of antifungal agents on zidovudine glucuronidation by human liver microsomes.

The Clinical Pharmacokinetics of Itraconazole: An Overview

Pesticides report 40: Bound xenobiotic in food commodities of plant and animal origin (Technical Report)

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