We studied the pharmacokinetics and metabolism of rimantadine hydrochloride (rimantadine) following single-dose oral and intravenous administration in mice and dogs. Absorption of the compound in mice was rapid. Maximum concentrations in plasma occurred at less than 0.5 h after oral administration, and the elimination half-life was 1.5 h. Peak concentrations in plasma following oral administration were markedly disproportional to the dose (274 ng/ml at 10 mg/kg, but 2,013 ng/ml at 40 mg/kg). The bioavailability after an oral dose of 40 mg/kg was 58.6%. Clearance was 4.3 liters/h per kg, and the volume of distribution was 7.6 liters/kg at 40 mg/kg. In contrast to the results observed in mice, absorption of the compound in dogs was slow. Maximum concentrations in plasma occurred at 1.7 h after oral administration, and the elimination half-life was 3.3 h. A further difference was that peak concentrations in plasma were approximately proportional to the dose. Following administration of a single oral dose of 5, 10, or 20 mg/kg, maximum concentrations in plasma were 275, 800, and 1,950 ng/ml, respectively. The bioavailability after an oral dose of 5 mg/kg was 99.4 o.The clearance was 3.7 liters/h per kg, and the volume of distribution was 13.8 liters/kg at 5 mg/kg. Mass balance studies in mice, using [methyl-'4CJrimantadine, indicated that 98.7% of the administered dose could be recovered in 96 h. Less than 5% of the dose was recovered as the parent drug in dog urine within 48 h. Finally, gas chromatography-mass spectrometry studies, done with mouse plasma, identified the presence of two rimantadine metabolites. These appeared to be ring-substituted isomers of hydroxyrimantadine.Rimantadine hydrochloride (rimantadine), which is chemically related to the anti-influenza A drug amantadine hydrochloride (amantadine, Symmetrel), has been reported to be effective against influenza A in human studies and in mouse model systems (2,7,11). It is being used in the USSR for both prophylaxis and therapy of influenza A infections (12).The pharmacokinetics and metabolism of rimantadine in humans have been reported (F. dine, which was then analyzed by gas chromatography (HP 5880A; Hewlett-Packard Co.) with an electron capture detector (6). PFB-amantadine was used as the internal standard and was prepared in house. The oven temperature was programmed for 240°C for 5 min, followed by a temperature gradient of 5°C/min for 6 min, to 270°C. The 6-ft (1.83-m) column was packed with 10% OV-1 (Ohio Valley Specialty Chemical, Inc.) on Chromasorb W (Hewlett-Packard Co.). The method was linear between 10 and 10,000 ng/ml in plasma-free solutions. The limit of detection was 5 ng/ml. However, linearity in biological solutions, such as plasma or tissue extracts, was restricted to a narrower range and was determined for each analysis. Samples were assayed only in the linear portion of the curve. Absolute recovery from plasma ranged from 54% at 50 ng/ml to 72% at 1,000 ng/ml. Reproducibility was 7% relative standard deviation. Rimantadine in plasma...

No abstract

No abstract

Specific cell-mediated immunity to SV40 tumor-specific transplantation antigen (TSTA) in BALB/c mice undergoing progressive tumorigenesis by syngeneic SV40-transformed cells (VLM) was investigated in vivo using a tumor-cell neutralization test. Specific cellular reactivity to SV40 TSTA was not detected in BALB/c mice bearing large tumors (10-15 mm mean diameter) but was demonstrable after tumor excision. Specific cytotoxic reactivity against syngeneic SV40-transformed cells in vivo could be restored to lymphoid cells from VLM tumor-bearing mice either by culturing the lymphoid cells in vitro or by treating them with papain or trypsin. Enzyme-treated lymphoid cells from MCA tumor-bearing BALB/c mice had no cytotoxic reactivity against VLM cells. These studies suggest that tumor-bearing hosts possess lymphocytes which are sensitized to the TSTA of the tumor but that the reactivity of these lymphocytes is blocked.