Tissue Distribution after Intravenous Dosing of Micafungin, an Antifungal Drug, to Rats

Abstract

Micafungin, a new echinocandin-like lipopeptide antifungal agent, has potent in vitro and in vivo activity against a variety of pathogenic Candida species and Aspergillus species by inhibiting the biosynthesis of 1,3-b-D-glucan, a major and specific component of the fungal cell wall, and its minimal inhibitory concentrations at which 90% of the isolates were inhibited (MIC 90 ) against Candida albicans, Candida tropicalis, Candida glabrata, Candida krusei, Aspergillus fumigatus, and Aspergillus flavus are less than 0.125 mg/ml.1-4) Micafungin has a significant therapeutic effect against deepseated mycoses caused by Candida or Aspergillus, the major pathogenic fungi. The clinical responses in trials that examined the safety and efficacy of micafungin monotherapy (micafungin dosage: 12.5-150 mg) in Japan were 60% in invasive pulmonary aspergillosis, 67% in clonic necrotizing pulmonary aspergillosis, 55% in pulmonary aspergilloma, 100% in candidiasis, and 71% in esophageal candidiasis. 2,5) It has been reported that micafungin exhibits linear pharmacokinetics after intravenous dosing to rats, mice, dogs, and rabbits, as well as humans. [6][7][8][9] The radioactivity after intravenous dosing of 14 C-labeled micafungin to male rats is widely distributed immediately and the radioactivity in tissues decreases almost in parallel with the radioactivity in plasma.10) Unchanged micafungin concentrations in rabbit tissues, including the liver, kidney, lungs, and spleen, at near peak plasma concentrations 30 min after the last of multiple doses over eight days are several-fold in excess of the MIC 90 against the clinical isolates of Candida spp. and Aspergillus spp. 7) However, there are few detailed studies on the tissue distribution kinetics of unchanged drug after an intravenous dose of micafungin in animals and humans.In the present study, we investigated the distribution kinetics in tissues, such as liver, kidney, and lungs, after an intravenous dose of micafungin to male rats. MATERIALS AND METHODS MaterialsMicafungin and internal standard (FR195743) 11) were synthesized and supplied by Fujisawa Pharmaceutical Co., Ltd. All other reagents were of the highest purity commercially available.Animal Studies Male Sprague-Dawley rats of 7 weeks of age and weighing between 287 and 318 g, obtained from Charles River Japan (Kanagawa, Japan), were used. During the experiments, the rats were housed at a temperature of 23Ϯ2°C and relative humidity of 55Ϯ5% with a 12-h night/day cycle. Micafungin sodium was dissolved in saline (1 mg/ml), and administered as a single intravenous bolus at a dose of 1 mg/kg. Blood and tissue (liver, kidney, and lung) samples were collected predose and at the following times after the dose: 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h. All blood samples were collected from the abdominal aorta under ether anesthesia and immediately centrifuged at 4°C to obtain the plasma. The plasma and tissue samples were frozen at Ϫ20°C until analysis. Determination of Micafungin in Plasma and TissuesThe plasma concentrat...

Pharmacokinetic Behavior of Micafungin in Rats with Carbon Tetrachloride-Induced Acute Hepatic Failure

“…22) The increased Vd ss of micafungin in CCl 4 -treated rats is an interesting observation, since the Vd ss of drugs is, in general, almost unaltered 11,14,18) or decreased 13) probably due to impairment of blood supply to peripheral tis- sue. In this connection, we assumed that the augmented uptake of micafungin to tissues would lead to an increase in the Vd ss regardless of the change in unbound fraction.…”

Tissue Penetration of Antifungal Agents

“…The vast majority of anidulafungin and micafungin found in the ELF is present within macrophages rather than in the fluid itself (58,61,62). Caspofungin, micafungin, and anidulafungin exhibit lung tissue exposures in rodents that exceed those in plasma by 1.1-fold, 2.8-fold, and 10-fold, respectively (102,103,150).…”

“…This is largely related to delayed clearance from the liver. However, micafungin appears to behave differently, with a lower peak concentration in the livers of rats and an AUC that is similar to that of the plasma (150). For caspofungin, specific hepatic transporters that mediate uptake into rat liver have been identified (26).…”

CD101, a novel echinocandin with exceptional stability properties and enhanced aqueous solubility

“…We used anidulafungin as the comparator in these studies not only because of the structural similarity to CD101, but also because anidulafungin has the longest plasma half-life of the approved echinocandins across species. [18][19][20][21][22] The unique chemical stability of CD101 has largely circumvented the main route of elimination (chemical degradation via ring opening) that is observed for anidulafungin and is likely a key contributor to the improved pharmacokinetics of CD101, although this alone may not entirely explain the long half-life that is observed in vivo across species (typically 3-fold to 5-fold longer than that of anidulafungin). 10 In addition, the lack of degradation and the absence of open-chain aldehyde formation suggest that CD101 may offer higher margins of safety with fewer dose-limiting toxicities over echinocandins that generate such reactive degradants.…”