Effect of cimetidine on the disposition of rimantadine in healthy subjects

Abstract

Twenty-three healthy male and female subjects received single 100-mg oral doses of rimantadine hydrochloride on two occasions in an open-label, sequential design with a 6-day washout between doses. The first dose of rimantadine was administered alone, and the second dose was administered concomitantly with cimetidine (300 mg four times a day for 6 days). Blood and urine samples were collected, and rimantadine concentrations were determined by a gas-chromatographic-mass-spectrometric method. There were no changes in the rate of absorption and the renal clearance of rimantadine when it was administered with cimetidine. Both parametric and nonparametric tests showed significant differences in the area under the concentration-time curve, apparent total clearance, and elimination rate constant between the treatments (P < 0.01). The apparent total clearance was reduced by 18%, resulting in higher values for the area under the concentration-time curve in the presence of cimetidine. However, the wide therapeutic index of rimantadine renders these changes of little, if any, clinical consequence.Rimantadine (oc-methyl-l-adamantanemethylamine hydrochloride), an analog of amantadine with equipotent antiviral activity (5, 6), is being evaluated for prophylaxis and treatment against influenza A viral infections (1, 2, 8-10, 13, 17). Rimantadine is extensively metabolized by the liver, and renal excretion of the parent drug and its metabolites is the major pathway of elimination (4, 14-16). Drugs which affect the hepatic microsomal enzyme systems have the potential for altering the metabolism of rimantadine, since the major pathway is hydroxylation. The histamine H2 receptor antagonist cimetidine is known to have an inhibitory effect on hepatic oxidative drug-metabolizing enzymes (12). Since rimantadine may be prescribed for patients taking cimetidine, the potential metabolic interaction between these two drugs provided the rationale for investigating the effect of cimetidine on the disposition of rimantadine. The aim of the present study was to compare the disposition of rimantadine after single 100-mg oral doses of rimantadine hydrochloride before and during cimetidine treatment in healthy subjects. MATERIALS AND METHODSTwenty-three healthy subjects (20 male and 3 female), ranging in age from 22 to 45 years and ranging in weight from 57 to 89 kg, participated in this study after giving their written, informed consent. Only females of non-child-bearing potential were admitted into the study. The subjects were in good general health as determined by base-line history, physical examination, hematologic examination, urinalysis, and determination of serum chemistries. The use of alcohol and over-the

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

“…plasma levels of RIM (100 mg p.o. dose) were from 0.005 to 0.8 µg/mL, with AUC values of approximately 3 µg × h/mL and T max values within 2-6 h by previous data (Wills et al, 1987;Holazo et al, 1989). Thus, the species differences of AMA and RIM disposition kinetics were remarkably observed between the previous data and our data.…”

“…In addition, in rats at an infusion of 3 mg/kg of [ 3 H]-AMA, the range of plasma concentration from 7 to 127 min varied between 0.9 and 0.3 µg/mL (Goralski et al, 1999). While Holazo et al (1989) investigated RIM assay in human plasma by GC-MS and their lower limits of quantification were much better (5 ng/mL), their method analyzed RIM in samples with large sample volumes (14 mL of blood), resulting in high costs. In addition, in mice at the p.o.…”

“…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.…”

Pharmacokinetics and Safety of Coadministered Oseltamivir and Rimantadine in Healthy Volunteers: An Open‐Label, Multiple‐Dose, Randomized, Crossover Study

“…Steady‐state plasma concentrations of oseltamivir carboxylate, the active metabolite of oseltamivir, are reached after approximately 3 days 23 . The pharmacokinetics of rimantadine 22 , 24 , 25 and oseltamivir 23 , 26 – 28 have been studied separately, but not in combination.…”

Photocatalytic degradation of three amantadine antiviral drugs as well as their eco-toxicity evolution

“…Therefore, the effect of pH value of the solution on the photocatalytic degradation rate of three antiviral drugs was studied. The pKa values of three antiviral drugs are 10.8, 10.8 and 10.4 for 1-amantadine, 2-amantadine and rimantadine, respectively [28], suggesting that they generally existed as protonation and neutral forms in water. Thus, the observed apparent rate constants in TiO 2 photocatalysis process were consisted of degradation of protonation and neural form of substrates, as shown in Eqs.…”