Micafungin is a novel, semisynthetic antifungal lipopeptide with an echinocandin-like chemical structure. This agent exerts its fungicidal action by inhibiting biosynthesis of 1,3-b-D-glucan, an essential component of the cell wall of most pathogenic fungi, leading to osmotic instability, and ultimately, cell rupture.1-3) Micafungin demonstrates potent antifungal activities against Candida spp. and Aspergillus spp. in vitro, and its therapeutic efficacy has been confirmed in the treatment of infectious disease caused by these fungi species.4,5) Because of its poor intestinal absorbability, micafungin is administered via an intravenous route in clinical practice. As urinary recovery of the unchanged form is less than 1% of the total dose, it is believed that micafungin is eliminated mainly by non-renal removal. 6,7) In view of the severity of disease conditions requiring antifungal therapy, micafungin is often administered to critically ill patients with hepatic damage. However, there have not been any reports regarding the impact of hepatic dysfunction on the disposition of micafungin, even though the total body clearance is probably dependent on the metabolic capacity of the liver.In the present study, we examined the pharmacokinetic behavior of intravenously administered micafungin in acute hepatic failure in a rat model intoxicated with carbon tetrachloride (CCl 4 ). MATERIALS AND METHODSReagents Standard solutions of micafungin and FR195743 (internal standard (IS) for HPLC) were generously donated by Fujisawa Pharmaceutical Co., Ltd. (Osaka, Japan). Sodium salt of micafungin for injection (Funguard TM , containing 50 mg micafungin per a vial) and cyclosporine for injection (Sandimmun TM , containing 250 mg cyclosporine per 5 ml ampoule) were purchased from Fujisawa Pharmaceutical Co., Ltd. and Novartis Pharma KK (Tokyo, Japan), respectively. CCl 4 was obtained from Attest (Kyoto, Japan). All other chemicals and solvents were of the highest quality commercially available.Experimental Animals and Treatment Male SpragueDawley rats were obtained from CLEA Japan, Inc (Tokyo, Japan). The rats were acclimatized for at least 2 d before assignment to experimental groups at 5-6 weeks of age (140-190 g), and were housed in a clean room maintained at 23Ϯ2°C with a relative humidity 55Ϯ10% and 12-h light/dark cycle. They were allowed free access to regular animal diet and drinking water except when fasted for 24 h before administration of micafungin. Acute hepatic failure in rats was induced by intraperitoneal injection of 50 % CCl 4 in olive oil (5 ml/kg) 24 h before administration of micafungin. The rats used in this study were handled in accordance with the Guidelines for Animal Experimentation of Shiga University of Medical Science, and the experimental protocol was approved by the Animal Care and Use Committee of the Research Center for Animal Life Science of this institution.Administration of Micafungin and Blood Collection Rats were anesthetized by ethyl ether, and a polyethylene cannula (outer diameter, 0.8 mm; i...

We examined whether the pharmacokinetic disposition of micafungin (MCFG), an echinocandin class antifungal agent, is altered in hyperbilirubinemia using a rat model prepared by bile duct ligation (BDL). Serum bilirubin levels were increased depending upon the duration of BDL. The elimination rate constant and total body clearance (CL(tot)) of MCFG were reduced by 24% and 16%, respectively, after BDL for 1 h, but there was no significant change in the apparent volume of distribution at steady-state. The degree of reduction in the CL(tot) was much greater 7 days after BDL as compared with that 1 h after BDL (44% vs. 16%). However, the proportion of the biliary clearance in the CL(tot) was about 10%. This is similar to the extent of decrease in the CL(tot) by occlusion of the bile duct, demonstrating that decreased biliary excretion of MCFG makes only a minor contribution to its pharmacokinetic change. These findings suggest that the metabolic capacity of MCFG is markedly impaired in hepatic hypofunction secondary to hyperbilirubinemia, providing a fundamental explanation for the previous clinical report that there is a significant correlation between dose-adjusted plasma MCFG concentration and serum bilirubin levels.

Change in the pharmacokinetic disposition of an antifungal agent micafungin (MCFG) by 8-hour plasma exchange (PE) with 3200 mL replacement was examined in a stem cell transplant recipient. On pharmacokinetic analysis of the time course of the serum concentrations of MCFG, it was determined that PE shortened the elimination half-life of MCFG from 16.5 hours to 6.3 hours. Total clearance (CL(tot)) was increased from 0.366 L/h to 0.932 L/h by PE. PE-dependent clearance (CL(pe)) accounted for approximately two-thirds of CL(tot), and PE was found to contribute to the removal of nearly 40% of the total body store of MCFG. It was confirmed that a significant amount of MCFG was excluded into apheresed plasma waste. In addition, adsorption of MCFG onto plasma-separating membrane was strongly suggested, because the CL(pe) exceeded the rate of plasma apheresis and MCFG concentrations in apheresed plasma were lower than those in circulating blood collected at the same time. The marked elimination of MCFG during PE can be explained by its low volume of distribution and high affinity for serum proteins. Judging from these findings as well as those of other reports, MCFG can be considered one of the drugs most susceptible to removal by PE. Our findings suggest that an increment in the regular dose of MCFG would be required at the next administration after PE.

A patient was admitted to the intensive care unit because of respiratory failure, and warfarin therapy was started at 2 mg/day for the treatment of pulmonary embolism, together with other medications. Despite the low dosage of warfarin, international normalized ratio (INR) was markedly elevated from 1.15 to 11.28 for only 4 days, and bleeding symptoms concurrently developed. Vitamin K2 was infused along with discontinuation of warfarin. One day later, the INR was found to have decreased, and bleeding was also improved. An objective causality assessment indicated a probable relationship between clotting abnormality and warfarin administration, although the degree of elevation of the INR was unusual in the light of the daily warfarin dose and duration of its exposure. Based on the clinical status of the patient, it was suspected that several conditions contributed to the abnormal hypersensitivity to warfarin. Contributory factors probably included pharmacokinetic interactions with co-administrated drugs, vitamin K deficiency caused by decreased dietary intake, reduced gut bacterial production, impaired intestinal absorption and hepatic synthetic capacity, and increased consumption of clotting factors. In view of our experience in the present case, it should be stressed that close monitoring of coagulation capacity is necessary in critically ill patients in order to avoid fatal haemorrhage after initiating warfarin therapy regardless of the dosage.