Relative Bioavailability of Rimantadine HCI Tablet and Syrup Formulations in Healthy Subjects

Wills, Robert J.; Choma, Nadia; Buonpane, Gerard; Lin, Amy; Keigher, Nancy

doi:10.1002/jps.2600761208

Cited by 7 publications

(8 citation statements)

References 13 publications

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“…2). DISCUSSION The values of the pharmacokinetic parameters for rimantadine in the absence of cimetidine dosing were consistent with those obtained in previous single-and multiple-dose studies in healthy subjects (14)(15)(16). Unlike the procedure in other interaction studies with cimetidine, in the present study the subjects were not pretreated with cimetidine prior to administration of the rimantadine dose.…”

Section: Resultssupporting

confidence: 90%

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Effect of cimetidine on the disposition of rimantadine in healthy subjects

Holazo

Choma

Brown

et al. 1989

Antimicrob Agents Chemother

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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

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Section: Resultssupporting

confidence: 90%

“…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)(15)(16). Drugs which affect the hepatic microsomal enzyme systems have the potential for altering the metabolism of rimantadine, since the major pathway is hydroxylation.…”

mentioning

confidence: 99%

Effect of cimetidine on the disposition of rimantadine in healthy subjects

Holazo

Choma

Brown

et al. 1989

Antimicrob Agents Chemother

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“…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.…”

Section: Application To Pharmacokinetic Study Of Ama and Rimsupporting

confidence: 71%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Higashi

Uemori

Fujii

2005

Biomed. Chromatogr.

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We investigated simultaneous high-performance liquid chromatographic (HPLC) determination of amantadine hydrochloride (AMA) and rimantadine hydrochloride (RIM) levels in rat plasma after fluorescent derivatization with o-phthalaldehyde and 2-mercaptoethanol. Afterwards, the method was applied to determine their pharmacokinetics. The retention times of AMA and RIM derivatives were 12.6 and 22.2 min and the lower limits of detection were 0.025 and 0.016 microg/mL, respectively. The coefficients of variation for intra- and inter-day assay of AMA and RIM were less than 5.1 and 7.6%, respectively. After i.v. administration of AMA or RIM to rats, the total body clearance and distribution volume at the steady-state of RIM were higher than those of AMA. Bioavailability of AMA and RIM was 34.9 and 37.2%, respectively. When AMA and RIM were p.o. co-administered, the area under the plasma concentration--time curve of RIM was significantly lower than that after RIM alone. On the other hand, pharmacokinetic parameters of AMA did not significantly change. These results indicate that our HPLC assay is simple, rapid, sensitive and reproducible for simultaneously determining AMA and RIM concentrations in rat plasma and is applicable to their pharmacokinetic studies. Also, co-administration of AMA and RIM may result in the lack of pharmacological effects of RIM.

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“…A number of assays have been reported for the determination of rimantadine in biological fluids [6][7][8][9][10][11][12][13][14][15], including gas chromatography with electron-capture detection (GC-ECD) [6,7], gas chromatography with mass spectrometry (GC-MS) [8][9][10][11][12][13], high-performance liquid chromatography with fluorescence detection (HPLC-Flu) [14,15] and high-performance liquid chromatography with ultraviolet detection (HPLC-UV) [16]. The various experiments described above usually require complicated derivatization treatment and liquid-liquid extraction to increase its sensitivity, or special facilities for the use of radioactive compounds.…”

Section: Introductionmentioning

confidence: 99%