Role of Plasma Proteins in Pharmacokinetics of Micafungin, an Antifungal Antibiotic, in Analbuminemic Rats

Abe, Fumie; Ueyama, Jun; Kawasumi, Noriyo; Nadai, Masayuki; Hayashi, Tateki; Kato, Mayumi; Ohnishi, Masafumi; Saito, Hiroko; Takeyama, Naoshi; Hasegawa, Takaaki

doi:10.1128/aac.00396-08

Cited by 15 publications

(13 citation statements)

References 16 publications

(28 reference statements)

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“…Therefore, the binding ability of MCFG may be relatively stable irrespective of changes in the plasma concentrations of albumin and MCFG within certain ranges. This notion is also supported by the previous report showing that there were no significant differences in the pharmacokinetic behavior of MCFG between analbuminemic and normal rats (Abe et al 2008). However, a slight increase in the Vd ss of MCFG was observed in phlebotomized rats.…”

Section: Discussionsupporting

confidence: 74%

Effect of blood decrease on micafungin disposition in rats

Konishi

Fukushima

Sudo

et al. 2011

Eur J Drug Metab Pharmacokinet

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Micafungin (MCFG) is a novel echinocandin-class antifungal agent that extensively undergoes metabolic removal in the liver. In the present study, the influence of decreased blood volume on pharmacokinetic disposition of MCFG was examined using a rat model prepared by phlebotomy. In phlebotomized rats, hematocrit level and plasma albumin concentration were decreased by 50 and 15%, respectively. Regarding the pharmacokinetic parameters of MCFG, there were no significant differences in the total body clearance (CL(tot)) and elimination rate constant (k (e)) between control and phlebotomized rat groups. A slight increase was observed in the apparent volume of distribution at steady-state (Vd(ss)), but the degree of change was minimal. These findings demonstrate that the elimination capacity for MCFG is only slightly affected by severe anemia and moderate hypoalbuminemia, and provide experimental evidence for the preceding clinical studies suggesting that neither hematocrit level nor serum albumin concentration is a contributory factor for the metabolic clearance of MCFG.

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Section: Discussionsupporting

confidence: 74%

Effect of blood decrease on micafungin disposition in rats

Konishi

Fukushima

Sudo

et al. 2011

Eur J Drug Metab Pharmacokinet

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“…Previous studies indicated that the pharmacokinetics of MCFG was not affected with a metabolism by sulfatase and cytochrome P450 or albumin. 9,25) Additionally, multidrug resistance-associated protein2 (ABCC2/Mrp2) is involved mainly in the hepatobiliary excretion of MCFG in rats. 26) Because bilirubin is also excreted into bile via Mrp2, 27) it could be possible that hepatobiliary excretion of MCFG via MRP2 is decreased in the patients with decreased hepatic functions.…”

Section: Discussionmentioning

confidence: 99%

The Impact of Total Bilirubin on Plasma Micafungin Levels in Living-Donor Liver Transplantation Recipients with Severe Liver Dysfunction

Iwamoto

Kagawa

Sakurai

et al. 2009

Biological & Pharmaceutical Bulletin

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Mcafungin (MCFG) is a semisynthetic antifungal echinocandin-like lipopeptide that inhibits the synthesis of 1,3-b-D-glucan, an essential polymeric polysaccharide in the cell wall of many pathogenic fungi.1,2) MCFG has superior antibacterial activity against Candida and Aspergillus species.3) Currently, this agent is commonly administered to prevent and treat deep-seated mycosis in patients with various diseases. [4][5][6][7][8] It is also administered to recipients of living-donor liver transplantations (LDLT) to prevent or treat invasive fungal infections. MCFG is metabolized primarily by sulfatase and cytochrome P450, and has low hepatic extraction ratio. Additionally, MCFG has very high protein binding (Ͼ99.5%) in plasma and 90% of MCFG administered and its metabolites are eliminated through the bile. 9)It is reported that MCFG has low mechanism-based toxicity because the inhibition of fungal cell wall synthesis effected by echinocandins has no relevance for mammalian cells.10,11) MCFG was reported to be well tolerated at doses from 2.5 to 150 mg/d in healthy male volunteers, suggesting that MCFG could be administered safely to most patients. 6)Furthermore, other reports have concluded that dose adjustment is not required for elderly patients or patients with moderate liver dysfunction or severe renal dysfunction. 9,12) However, little is known about the pharmacokinetic or pharmacodynamic changes of MCFG in LDLT-recipients with extremely unstable liver function. In the present study, we measured the plasma concentration of MCFG in 20 recipients of LDLT and evaluated the clinical effects and safety of MCFG using biochemical parameters. MATERIALS AND METHODS PatientsThe subjects in this study were 20 patients who visited the Department of Hepatobiliary Pancreatic Surgery of Mie University Hospital between April 2003 and March 2007. After receiving a LDLT, these patients were diagnosed with fungal infections according to a rise in b-D-glucan (BDG) or a positive reaction to an Aspergillus antigen. Written informed consent was obtained for this study from all subjects or their families. In addition, the Ethics Committee of our university gave its approval for this study. MCFG Infusion and Blood SamplingThe subjects received MCFG as treatment for their fungal infections. MCFG was administered by a constant infusion for 60 min via a peripheral venous catheter, once daily, at doses of 100-300 mg. When the blood MCFG concentration reached a steady state, the patient's blood samples were taken before (trough) and an hour after (peak) the drip infusion of MCFG. The blood was centrifuged at 2100ϫg for 20 min at room temperature, and the plasma was separated and kept at Ϫ80°C until analysis.Determination of Plasma Micafungin MCFG solution (100 mg/ml) and FR195743 solution (internal standard (IS); 100 mg/ml) were donated by Astellas Pharma Inc. (Tokyo). All other reagents were of the highest grade available. The plasma concentrations of MCFG were determined by high performance liquid chromatography (HPLC) according to the ...

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“…The pharmacodynamic parameters in plasma were derived from the free (i.e., unbound) drug concentrations as well as total (i.e., unbound plus bound) drug concentrations. Although the presence of protein increases the MIC of micafungin (29), the effect of protein binding on clinical outcomes is unknown (1,29,31). The MIC 90 value for A. fumigatus was obtained from the recent literature (43).…”

Section: Methodsmentioning

confidence: 99%