Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

Ashbee, H. Ruth; Gilleece, Maria

doi:10.1038/bmt.2011.146

Cited by 30 publications

(26 citation statements)

References 185 publications

(166 reference statements)

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“…2). Consistent with our results, interaction between AMB and P-gp has been suggested by other pieces of evidence from studies on animal intestines (13,14,25). In a study by Ishizaki and colleagues, the oral bioavailability of cyclosporine was decreased after coadministration of AMB in Wistar rats, presumably due to the increased P-gp expression induced by AMB at the duodenum (14).…”

Section: Discussionsupporting

confidence: 80%

In Vitro and In Vivo Evidence for Amphotericin B as a P-Glycoprotein Substrate on the Blood-Brain Barrier

Shao

Wang

et al. 2014

Antimicrob Agents Chemother

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dAmphotericin B (AMB) has been a mainstay therapy for fungal infections of the central nervous system, but its use has been limited by its poor penetration into the brain, the mechanism of which remains unclear. In this study, we aimed to investigate the role of P-glycoprotein (P-gp) in AMB crossing the blood-brain barrier (BBB). The uptake of AMB by primary brain capillary endothelial cells in vitro was significantly enhanced after inhibition of P-gp by verapamil. The impact of two model P-gp inhibitors, verapamil and itraconazole, on brain/plasma ratios of AMB was examined in both uninfected CD-1 mice and those intracerebrally infected with Cryptococcus neoformans. In uninfected mice, the brain/plasma ratios of AMB were increased 15 min (3.5 versus 2.0; P < 0.05) and 30 min (5.2 versus 2.8; P < 0.05) after administration of verapamil or 45 min (6.0 versus 3.9; P < 0.05) and 60 min (5.4 versus 3.8; P < 0.05) after itraconazole administration. The increases in brain/plasma ratios were also observed in infected mice treated with AMB and P-gp inhibitors. The brain tissue fungal CFU in infected mice were significantly lower in AMB-plus-itraconazole or verapamil groups than in the untreated group (P < 0.005), but none of the treatments protected the mice from succumbing to the infection. In conclusion, we demonstrated that P-gp inhibitors can enhance the uptake of AMB through the BBB, suggesting that AMB is a P-gp substrate. Fungal infection of the central nervous system (CNS) is one of the most deadly forms of invasive fungal diseases. The most common pathogens that involve the CNS included Cryptococcus neoformans, Candida spp., and Aspergillus spp., while numerous other fungi had been reported as less common causes. New-generation triazoles with both broad antifungal spectrum and good CNS penetration, such as voriconazole and posaconazole, have expanded the choice for treatment of CNS fungal infections (1). Nonetheless, amphotericin B (AMB) remains the drug of choice for many forms of CNS fungal infection. In fact, AMB is strongly recommended for treatment of CNS cryptococcosis, histoplasmosis, blastomycosis, and mucormycosis (2). AMB plus flucytosine has demonstrated favorable efficacy in AIDS-associated cryptococcal meningitis and has been recommended as the first-line induction therapy (3). Ironically, AMB is well known for its poor ability to penetrate the blood-brain barrier (BBB), as the concentrations in the cerebrospinal fluid and brain tissue are almost undetectable (4). This has posed a dilemma to physicians dealing with CNS fungal infections using AMB, because increasing the dose of AMB in an effort to raise the CNS concentration would aggravate the severity of its multisystemic peripheral toxicities, especially nephrotoxicity.The manipulation of AMB penetration at the BBB is one strategy to improve outcome in CNS fungal infections, since the ability of antifungal drugs to achieve adequate concentrations in the CNS is one of the key factors influencing efficacy. However, despite advances in the understa...

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Section: Discussionsupporting

confidence: 80%

In Vitro and In Vivo Evidence for Amphotericin B as a P-Glycoprotein Substrate on the Blood-Brain Barrier

Shao

Wang

et al. 2014

Antimicrob Agents Chemother

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“…have resulted in a rise in life threatening co-conditions like invasive fungal infections (IFIs). Several triazole anti-fungal agents such as fluconazole, ketonazole, itraconazole, voriconazole and posaconazole are used for treatment to improve the therapeutic efficacy [1]. Voriconazole (Vrc), a structural derivative of fluconazole, is a second-generation triazole with broad-spectrum antifungal activity.…”

Section: Introductionmentioning

confidence: 99%

Plasma Voriconazole Estimation by HPLC

2015

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Voriconazole, an antifungal drug exhibiting wide inter-individual variability, is an ideal candidate for therapeutic drug monitoring (TDM). The aim of the present study was to standardize a simple, sensitive and rapid high performance liquid chromatography (HPLC) method with ultraviolet detection to determine plasma voriconazole concentration. The HPLC method consisted of a combination of acetonitrile and water (7:3) as mobile phase with 1 ml/min flow rate and detection at 255 nm. Plasma protein precipitation was carried out using perchloric acid and the filtered supernatant was passed through C18 column (250 9 4.6 mm, 5 lm) for the separation of voriconazole. The limit of quantification of voriconazole was 0.2 mg/L. The assay was validated with a linearity of 0.2-15 mg/L and used clinically for TDM in patient samples. The interassay precision was below 15 % for routine quality control samples. Weight based voriconazole doses were prescribed to 26 patients for empirical treatment of invasive fungal infections. Voriconazole therapy was managed from the baseline drug levels and follow up analysis reflected achievement in clinical efficacy. Routine TDM of voriconazole may reduce adverse events and improve the treatment response in invasive fungal infections.

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“…Polymorphism may ultimately affect drug effi cacy: CYP2C19 variation leads to a fi vefold variation in voriconazole levels between individuals. In the future, routine provision of pharmacogenomic data for new drugs together with accumulating knowledge about established agents will challenge physicians to assimilate and apply that information in drug prescribing (Ashbee and Gilleece 2011 ).…”

Section: Personalized Management Of Fungal Infectionsmentioning

confidence: 99%

Textbook of Personalized Medicine

Jain¹

2015

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Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

Cited by 30 publications

References 185 publications

In Vitro and In Vivo Evidence for Amphotericin B as a P-Glycoprotein Substrate on the Blood-Brain Barrier

In Vitro and In Vivo Evidence for Amphotericin B as a P-Glycoprotein Substrate on the Blood-Brain Barrier

Plasma Voriconazole Estimation by HPLC

Textbook of Personalized Medicine

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