Effect of fluconazole on the disposition of phenytoin

Blum, Robert A.; Wilton, John H.; Hilligoss, Donald M.; Gardner, Mark; Henry, Eugenia B.; Harrison, Nedra J.; Schentag, Jerome J.

doi:10.1038/clpt.1991.49

Cited by 108 publications

(47 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The coadministration of CLO with low therapeutic index compounds in which clearance primarily depends on CYP2C19 may thus be potentially hazardous. Previous studies showed inhibitory interactions between MIC and CYP3A4, 2A6, and 2C9 in vitro and in vivo (Blum et al, 1991;Maurice et al, 1992;Black et al, 1996;Draper et al, 1997;Laine et al, 2000). Our data show that in addition to these, MIC potently inhibits CYP2C19, 2D6, 2B6, and less so CYP1A2 in vitro in cDNA-expressing microsomes.…”

Section: Discussionsupporting

confidence: 58%

“…In keeping with the lack of CYP3A selectivity of CLO, MIC has been shown to strongly inhibit both CYP3A and CYP2A6 in vitro (Maurice et al, 1992;Draper et al, 1997). Moreover, in vivo both fluconazole and MIC have shown to potently inhibit CYP2C9, as demonstrated by clinically significant drug interactions observed in the presence of concomitant CYP2C9 substrates, including warfarin and phenytoin (Blum et al, 1991;Black et al, 1996;Laine et al, 2000;Venkatakrishnan et al, 2000 Ballard et al, 1988). The P450 interaction profile of SUL is largely unknown, with further studies necessary.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of Cytochromes P450 by Antifungal Imidazole Derivatives

Zhang

Ramamoorthy²,

Kilicarslan³

et al. 2002

Drug Metab Dispos

232

168

View full text Add to dashboard Cite

show abstract

Section: Discussionsupporting

confidence: 58%

mentioning

confidence: 99%

Inhibition of Cytochromes P450 by Antifungal Imidazole Derivatives

Zhang

Ramamoorthy²,

Kilicarslan³

et al. 2002

Drug Metab Dispos

232

168

View full text Add to dashboard Cite

show abstract

“…Therefore it is possible to speculate that fluconazole and voriconazole, but not micafungin, would clinically cause drug interactions with other drugs, which are metabolized by CYP2C9 or CYP2C19 as well as CYP3A4. It has been reported that the plasma concentrations of phenytoin and S-warfarin, which are mainly metabolized by CYP2C9, 39) are enhanced by coadministration of fluconazole, 15,46,47) and that voriconazole increases the plasma concentrations of phenytoin. 48) Mechanism-based inactivators have been reported to exhibit preincubation time dependence of inhibition.…”

Section: Discussionmentioning

confidence: 99%

Effect of Antifungal Drugs on Cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 Activities in Human Liver Microsomes

Niwa

Shiraga

Takagi

2005

Biological & Pharmaceutical Bulletin

231

151

View full text Add to dashboard Cite

Cytochrome P450s (CYP) comprise a superfamily of enzymes that catalyzes the oxidation of a wide variety of xenobiotic chemicals, including drugs and carcinogens. [3][4][5] Multiple-drug therapy is a common therapeutic practice, particularly in patients with several diseases or conditions, and many drug-drug interactions involving metabolic inhibition are reported. 6,7) Antifungal drugs, including fluconazole, itraconazole, micafungin, miconazole, and voriconazole ( Fig. 1), are widely used in the treatment of systemic candidal infections and mycoses. The mechanism of action of these antifungal drugs is the inhibition of fungal CYP (14a-sterol demethylase), an enzyme responsible for the conversion of lanosterol to 14a-demethyllanosterol in the ergosterol biosynthetic pathway, 8,9) except that micafungin inhibits 1,3-b-D-glucan synthase, leading to disruption of the growing fungal cell wall and death of the fungal cell.10,11) Because antibiotics, including antifungal drugs, are coadministered in most cases, the possibility of interactions between them and other drugs exists. Recently, we have investigated the effects of antifungal drugs excluding voriconazole on CYP3A4 activity and multidrug resistance protein 1 (MDR1), and found that itraconazole and miconazole, as well as ketoconazole, had greater inhibitory effects on both CYP3A4 metabolic and MDR1 transport activities than fluconazole and micafungin.12) In addition, it has been demonstrated that the K i values of fluconazole and micafungin against nifedipine oxidation activity, a marker enzyme activity of CYP3A4, are 10.7 mM and 17.3 mM, respectively.13) Zhang et al. 14) reported that miconazole competitively inhibits several CYPs, including CYP2C9, CYP2C19, and CYP3A4, with K i values ranging from 0.01 to 7.3 mM. Furthermore, it is likely that fluconazole and voriconazole inhibit CYP2C9, CYP2C19, and CYP3A4. Post-marketing Development Research Center, Fujisawa Pharmaceutical Co., Ltd.; 3-4-7 Doshomachi, Chuo-ku, Osaka 541-8514, Japan: and b Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd.; 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. Received March 22, 2005; accepted May 31, 2005 The effects of five antifungal drugs, fluconazole, itraconazole, micafungin, miconazole, and voriconazole, on cytochrome P450 (CYP) 2C9-mediated tolbutamide hydroxylation, CYP2C19-mediated S-mephenytoin 4-hydroxylation, and CYP3A4-mediated nifedipine oxidation activities in human liver microsomes were compared. In addition, the effects of preincubation were estimated to investigate the mechanism-based inhibition. The IC 50 value against tolbutamide hydroxylation was the lowest for miconazole (2.0 m mM), followed by voriconazole (8.4 m mM) and fluconazole (30.3 m mM). Similarly, the IC 50 value against S-mephenytoin 4-hydroxylation was the lowest for miconazole (0.33 m mM), followed by voriconazole (8.7 m mM) and fluconazole (12.3 m mM). On the other hand, micafungin at a concentration of 10 or 25 m mM neither inhibited nor ...

show abstract

“…Fluconazole is an inhibitor of the cytochrome P450 isoenzymes CYP2C9 and CYP2C19, the principal metabolising enzymes for PHT (9,133). The coadministration of fluconazole and PHT can be expected to be associated with a clinically significant increase in PHT plasma concentrations, and these may require adjustment to maintain safe therapeutic concentrations (134). Most of the second-generation AEDs, such as VGB, LTG, TGB, LEV, OXC, ZNS, and GBP, are not substrates of either CYP2C9 or CYP2C19 and are therefore unlikely to interact with fluconazole.…”

Section: Antifungal Agentsmentioning

confidence: 99%

The Importance of Drug Interactions in Epilepsy Therapy

et al. 2002

View full text Add to dashboard Cite

Summary: Long-term antiepileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to control seizures effectively, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. The fact that over-the-counter drugs and nutritional supplements are increasingly being self-administered by patients also must be considered. Therefore the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and on drug discontinuation. Although pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine (LTG) and valproic acid (VPA); these drugs exhibit synergistic efficacy when coadministered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions, and enzyme-inducing drugs such as phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) will readily enhance the metabolism of other AEDs [e.g., LTG, topiramate (TPM), and tiagabine (TGB)].The enzyme-inducing AEDs also enhance the metabolism of many other drugs (e.g., oral contraceptives, antidepressants, and warfarin) so that therapeutic efficacy of coadministered drugs is lost unless the dosage is increased. VPA inhibits the metabolism of PB and LTG, resulting in an elevation in the plasma concentrations of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of CBZ by VPA results in an elevation of the metabolite CBZepoxide, which also increases the risk of toxicity. Other examples include the inhibition of PHT and CBZ metabolism by cimetidine and CBZ metabolism by erythromycin. In recent years, a more rational approach has been taken with regard to metabolic drug interactions because of our enhanced understanding of the cytochrome P450 system that is responsible for the metabolism of many drugs, including AEDs. The review briefly discusses the mechanisms of drug interactions and then proceeds to highlight some of the more clinically relevant drug interactions between AEDs and between AEDs and non-AEDs. Understanding the fundamental principles that contribute to a drug interaction may help the physician to better anticipate a drug interaction and allow a graded and planned therapeutic response and, therefore, help to enhance the management of patients with epilepsy who may require treatment with polytherapy regimens.

show abstract

Effect of fluconazole on the disposition of phenytoin

Cited by 108 publications

References 0 publications

Inhibition of Cytochromes P450 by Antifungal Imidazole Derivatives

Inhibition of Cytochromes P450 by Antifungal Imidazole Derivatives

Effect of Antifungal Drugs on Cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 Activities in Human Liver Microsomes

The Importance of Drug Interactions in Epilepsy Therapy

Contact Info

Product

Resources

About