Pharmacokinetics and metabolism of rimantadine hydrochloride in mice and dogs

Abstract

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...

Simultaneous determination of amantadine and rimantadine by HPLC in rat plasma with pre-column derivatization and fluorescence detection for pharmacokinetic studies

“…In addition, in mice at the p.o. dose of 10 mg/kg of [ 14 C]-RIM, the range of plasma concentration from 1 to 6 h varied between 0.3 and 0.015 µg/mL (Hoffman et al, 1988). The measurable range of AMA and RIM by our method almost fully covers the previous values described above, indicating that our HPLC assay may be very suitable for the pharmakokinetic study of AMA using samples at a small volume (50 µL) and not using a radioactive compound.…”

“…In mice, the CL tot and BA values of RIM were 4.3 L/h/kg and 58.6%, respectively, using [ 14 C]-RIM. In dogs, they were 3.7 L/h/kg and 99.4%, respectively (Hoffman et al, 1988). In humans, the Each value represents the mean ± SD of six to eight rats.…”

“…The pharmacokinetics in humans and transport studies using animal tissues have been investigated mainly using GC-MS and [ 14 C]-RIM (Wills et al, 1987;Hoffman et al, 1988;Spector, 1988;Holazo et al, 1989). In the various experiments described above, complicated equipment and special facilities for using radioactive compounds are necessary.…”

Antioxidant Properties of Rimantadine in Influenza Virus Infected Mice and in Some Model Systems

“…The metabolism of Rim by the liver monooxy genases (Hoffman et al, 1988) which results in products with antioxidant effect is another pos sible cause for the in vivo effects.…”

Simultaneous liquid chromatographic assay of amantadine and its four related compounds in phosphate-buffered saline using 4-fluoro-7-nitro-2,1,3-benzoxadiazole as a fluorescent derivatization reagent

“…(Spector, 1988;Goralski et al, 1999;Hoffman et al, 1988). In the various experiments, complicated equipment and special facilities for using radioactive 424 Y.…”