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...

1. The absorption, distribution and excretion of nilvadipine have been studied in male rats and dogs after an i.v. (1 mg/kg for rats, 0.1 mg/kg for dogs) and oral dose (10 mg/kg for rats, 1 mg/kg for dogs) of 14C-nilvadipine. 2. Nilvadipine was rapidly and almost completely absorbed after oral dosing in both species; oral bioavailability was 4.3% in rats and 37.0% in dogs due to extensive first-pass metabolism. The ratios of unchanged drug to radioactivity in plasma after oral dosing were 0.4-3.5% in rats and 10.4-22.6% in dogs. The half-lives of radioactivity in plasma after i.v. and oral dosing were similar, i.e. 8-10 h in rats, estimated from 2 to 24 h after dosing and 1.5 d in dogs, estimated from 1 to 3 d. In contrast, plasma concentrations of unchanged drug after i.v. dosing declined biexponentially with terminal phase half-lives of 1.2 h in rats and 4.4 h in dogs. 3. After i.v. dosing to rats, radioactivity was rapidly distributed to various tissues, and maintained in high concentrations in the liver and kidneys. In contrast, after oral dosing to rats, radioactivity was distributed mainly in liver and kidneys. 4. With both routes of dosing, urinary excretion of radioactivity was 21-24% dose in rats and 56-61% in dogs, mainly in 24 h. After i.v. dosing to bile duct-cannulated rats, 75% of the radioactive dose was excreted in the bile. Only traces of unchanged drug were excreted in urine and bile.

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1. The metabolic profiles of nilvadipine in the excreta of male rats and dogs were studied after i.v. and oral dosing. Six types of metabolites were isolated and identified from the urine of male rats and dogs or bile of rats. 2. Several metabolites were detected in the urine (12) and bile (17) of rats by two-dimensional t.l.c., after dosing with 14C-nilvadipine. The metabolic profiles in the excreta of rats and dogs were qualitatively similar but quantitative differences were observed. 3. The main metabolites were products of (i) oxidation of the 1,4-dihydropyridine ring to the corresponding pyridine, (ii) hydrolysis of the 5-isopropyl ester or 3-methyl ester group to carboxylic acid, and/or (iii) hydroxylation of the 6-methyl group or methyl group of the isopropyl ester chain. 4. Minor metabolites were products of hydrolysis from the 5-isopropyl ester to the carboxylic acid having a dihydropyridine ring, or reduction of the 3-nitro group of the phenyl moiety having a pyridine ring.

The antitumor effects of FK317, a novel substituted dihydrobenzoxazine, were evaluated using human tumor xenografts (small cell lung cancer, non-small cell lung cancer, stomach cancer, colon cancer, pancreatic cancer, breast cancer, cervical cancer and ovarian cancer). Tumor growthinhibitory effects and the effective dose-range of FK317 were much stronger and broader, respectively, than those of reference drugs such as mitomycin C, adriamycin, cisplatin, taxol and irinotecan. Furthermore, the body weight decrease and myelosuppression in FK317-treated mice were less than in the animals given any of the reference drugs. To explain this tumor selectivity, the distribution of FK317 was investigated after dosing tumor-bearing mice with the 14 C-labelled compound. The concentration of FK317 in tumor tissues was relatively low, and long tumor retention was not observed. However, thin-layer chromatographic separation revealed that the radioactivity in the tumor resided mainly in strongly cytotoxic metabolites, while that in other tissues resided mainly in non-cytotoxic metabolites. These results suggest that FK317 shows strong antitumor activity without side effects, and one reason for this is its specific metabolite pattern. FK317 is now undergoing phase I clinical trials. Key words:FK317 -Antitumor effect -Human tumor xenograft -Selective toxicityMitomycin C A potent antineoplastic agent, FK973, 11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo-[7.4.1.0 2,7 .0 10,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate, was obtained by chemical modification of the novel antibiotic FR900482, which was isolated from the fermentation products of Streptomyces sandaensis No. 6897.1-3) This compound has a unique chemical structure including a hydroxylamine function, whose hydroxyl group forms an intramolecular hemiketal moiety. The antitumor activity of FK973 is equivalent to, or more potent than, those of mitomycin C (MMC), adriamycin (ADR) and cisplatin (CDDP) against murine tumors and human xenografts in mice, and its hematotoxic and myelosuppressive effects are weaker than those of MMC in mice.4) FK973 showed good efficacy in clinical studies, but its development was terminated because of a vascular leak syndrome (VLS) side effect which was characterized by pericardial and pleural effusion, ascites and subcutaneous edema. 5,6) Various FK973 derivatives were synthesized in an attempt to isolate the antitumor activity of FK973 from the VLS side effect, and FK317, 11-acetyl-8-carbamoyloxymethyl-4-formyl-6-methoxy-14-oxa-1, 11-diazatetracyclo-[7.4.1.0 2, 7 .0 10, 12 ]tetradeca-2,4,6-trien-9-yl acetate, was selected for further examination. FK317 showed similar antitumor activity to FK973, but did not induce pleural effusion in rats.7) FK317 contains an aziridine ring and a carbamoyl moiety, which are also present in MMC. MMC is a "bioreductive alkylating agent," which causes damage to DNA after reductive activation of the prodrug to form a DNA-reactive species.8, 9) FK317 also forms DNA-DNA interstrand and DNA-protein...

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