Skip to main content
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems
  • Log in
  • My alerts
  • My Cart

Main menu

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • COVID-19 Special Collection
    • Archive
    • Minireviews
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About AAC
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • AAC Podcast
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
  • ASM
    • Antimicrobial Agents and Chemotherapy
    • Applied and Environmental Microbiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems

User menu

  • Log in
  • My alerts
  • My Cart

Search

  • Advanced search
Antimicrobial Agents and Chemotherapy
publisher-logosite-logo

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • COVID-19 Special Collection
    • Archive
    • Minireviews
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About AAC
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • AAC Podcast
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
Antiviral Agents

Lack of Pharmacokinetic Interaction between the Oral Anti-Influenza Prodrug Oseltamivir and Aspirin

Charles Oo, Joanne Barrett, Albert Dorr, Baolian Liu, Penelope Ward
Charles Oo
1F. Hoffman-La Roche, Nutley, New Jersey
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: charles.oo@roche.com
Joanne Barrett
2Roche Global Development, Welwyn,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Albert Dorr
1F. Hoffman-La Roche, Nutley, New Jersey
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Baolian Liu
1F. Hoffman-La Roche, Nutley, New Jersey
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Penelope Ward
3GlaxoSmithKline, Brentford, Middlesex, United Kingdom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1128/AAC.46.6.1993-1995.2002
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

ABSTRACT

Twelve volunteers completed a two-sequence, three-way crossover study of a single 900-mg aspirin dose and multiple doses of 75 mg of oseltamivir in the absence and presence of 900 mg of aspirin. The plasma and urine results demonstrated no pharmacokinetic interaction between oseltamivir and aspirin.

Oseltamivir is a highly bioavailable (80%) ester prodrug of its active metabolite oseltamivir carboxylate, which is a potent and selective inhibitor of the neuraminidase enzyme of influenza A and B viruses (2). Oseltamivir is approved in the United States and Japan for the treatment of influenza A and B infection in adults and children ≥1 year old. Oseltamivir is metabolized to the carboxylate by high-capacity carboxylesterase in the liver (2, 6). After reaching a maximum, concentrations of oseltamivir in plasma quickly decline (half-life of 1 to 3 h), while levels of the carboxylate decline more slowly (half-life of 6 to 10 h). Approximately 60 to 80% of an oral dose of oseltamivir is excreted in the urine as the carboxylate. Once absorbed, aspirin is rapidly hydrolyzed by esterases in the gut wall, liver, plasma, and red blood cells to form salicylic acid, with a half-life of only 15 to 30 min (5). Salicylic acid is predominantly eliminated by competing hepatic conjugative and oxidative metabolic processes, while one of its metabolites, salicyluric acid, is secreted into the urine (4, 5). Because of the shared route of metabolism and excretion, drug interaction between oseltamivir and aspirin is theoretically possible. The purpose of this study was to evaluate whether such an interaction exists.

Twelve healthy subjects (eight males and four females) with a mean age of 36 ± 9 years, mean body weight of 73 ± 15 kg, and mean calculated creatinine clearance of 96 ± 19 ml/min participated in a three-way crossover study. The subjects were randomized into one of two sequence groups, ABC or BCA, and all subjects received two doses of 900 mg of aspirin and nine doses of 75 mg of oseltamivir (twice daily for 4 days plus a single dose the subsequent day) as shown in Table 1. On days 1, 8, and 9 for group ABC and days 4, 5, and 9 for group BCA, a 5- to 7.5-ml blood sample was collected from each subject predose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18, and 24 h postdose. Urine samples were collected on the same days predose and 0 to 4, 4 to 8, 8 to 12, and 12 to 24 h after drug administration.

The assay for concentrations of oseltamivir and the carboxylate in plasma and urine has been reported previously (7). Plasma aspirin, salicylic acid, and salicyluric acid and urine salicylic acid and salicyluric acid were isolated by liquid-liquid extraction. One third of samples taken for the aspirin analysis contained additional decomposition peaks that interfered with quantitation. The quality of the determinations for plasma and urine salicylic acid and salicyluric acid was satisfactory, and the coefficients of variation were ≤10%. Pharmacokinetic parameters were derived from the resulting data by using noncompartmental methods. For aspirin and its metabolites, an analysis of variance appropriate for this design was performed, including terms for sequence, subjects within sequence, period, and regimen. For oseltamivir and the carboxylate, there was no term for period since period and regimen were completely confounded. Area under the plasma concentration-time curve (AUC) and maximum concentration (Cmax) of the major metabolites, carboxylate and salicylic acid, were considered the primary parameters, and analysis was performed with natural logarithm-transformed data.

Because of assay interference, pharmacokinetic parameters for aspirin were not determinable. Plasma concentration-time profiles and mean pharmacokinetic parameters of the major metabolites, the carboxylate and salicylic acid, in the absence and presence of concomitant drug are displayed in Tables 2 and 3 and Fig. 1 and 2. The ratio of the means (C/B or C/A) and corresponding 90% confidence intervals for the primary parameters, Cmax and AUC from 0 to 12 h (AUC0-12), of the carboxylate and salicylic acid were within the 80-to-125% bioequivalence range when given separately or in combination, indicating a lack of interaction. Similarly, the AUC0-12 values and 90% confidence intervals of oseltamivir were within the bioequivalence range, while the Cmax of oseltamivir was higher in the presence of aspirin; this is considered likely due to intrasubject variability. The ratio of the means and corresponding 90% confidence intervals for Cmax and AUC0-∞ of salicyluric acid in the absence and presence of oseltamivir were also within the 80-to-125% bioequivalence range. The urinary excretion of oseltamivir, the carboxylate, salicylic acid, and salicyluric acid were comparable in the absence and presence of concomitant drug (Tables 2 and 3). The primary pharmacokinetic parameters of salicylic acid were equivalent in the presence and absence of oseltamivir; thus, it is reasonable to conclude the absence of an interaction between oseltamivir and aspirin in terms of hepatic esterase conversion. This finding is consistent with literature reports, since although metabolic drug interactions involving aspirin hydrolysis are theoretically possible, no studies to date have shown conclusively that aspirin hydrolysis is altered by coadministered drugs (4).

Renal elimination plays a minor role in the elimination of salicylic acid (<16%) (1), and hence the potential for competing with the carboxylate via the renal tubular secretory pathway is low. In contrast, renal excretion plays a significant role in the elimination of salicyluric acid (∼60%) (1). Hence, pharmacokinetics of salicyluric acid has a greater potential to interact with the anionic tubular secretion pathway, which is the major route of elimination of the carboxylate. In this study, the major plasma pharmacokinetic parameters of oseltamivir (AUC only), the carboxylate, salicylic acid, and salicyluric acid were bioequivalent in the absence and presence of concomitant drug, as were the comparability of the urine parameters. These results demonstrate that there was no interaction at the anionic tubular secretion pathway, confirming the low potential for interaction between oseltamivir and other agents at the level of the anionic tubular transporter (3).

FIG. 1.
  • Open in new tab
  • Download powerpoint
FIG. 1.

Mean (± standard deviation) steady-state plasma concentration-versus-time profiles of oseltamivir carboxylate in the absence and presence of aspirin.

FIG. 2.
  • Open in new tab
  • Download powerpoint
FIG. 2.

Mean (± standard deviation) single-dose plasma concentration-versus-time profiles of salicylic acid in the absence and presence of oseltamivir.

View this table:
  • View inline
  • View popup
TABLE 1.

Overall study design

View this table:
  • View inline
  • View popup
TABLE 2.

Steady-state pharmacokinetic parameters of oseltamivir carboxylate and oseltamivir in the absence and presence of aspirin

View this table:
  • View inline
  • View popup
TABLE 3.

Single-dose pharmacokinetic parameters of salicylic acid and salicyluric acid in the absence and presence of oseltamivir

FOOTNOTES

    • Received 15 October 2001.
    • Returned for modification 4 January 2002.
    • Accepted 11 March 2002.
  • Copyright © 2002 American Society for Microbiology

REFERENCES

  1. 1.↵
    Dubovska, D., V. K. Piotrovskij, M. Gajdos, Z. Krivosikova, V. Spustova, and T. Trnovec. 1995. Pharmacokinetics of acetylsalicylic acid and its metabolites at low doses: a compartmental modeling. Methods Find. Exp. Clin. Pharmacol.17:67-77.
    OpenUrlPubMedWeb of Science
  2. 2.↵
    He, G., J. Massarella, and P. Ward. 1999. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin. Pharmacokinet.37:471-484.
    OpenUrlCrossRefPubMedWeb of Science
  3. 3.↵
    Hill, G., T. Cihlar, C. Oo, E. S. Ho, K. Prior, H. Wiltshire, J. Barrett, B. Liu, and P. Ward. 2002. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion—correlation of in vivo and in vitro studies. Drug Metab. Dispos.30:13-19.
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    Minors, J. O. 1989. Drug interactions involving aspirin (acetylsalicylic acid) and salicylic acid. Clin. Pharmacokinet.17:327-344.
    OpenUrlPubMedWeb of Science
  5. 5.↵
    Needs, C. J., and P. M. Brooks. 1985. Clinical pharmacokinetics of salicylates. Clin. Pharmacokinet.10:164-177.
    OpenUrlCrossRefPubMedWeb of Science
  6. 6.↵
    Oo, C., J. Barrett, G. Hill, J. Mann, A. Dorr, R. Dutkowski, and P. Ward. 2001. Clinical pharmacokinetics and dose recommendation of oseltamivir suspension for the treatment of influenza in children. Paediatr. Drugs3:229-236.
    OpenUrlCrossRefPubMed
  7. 7.↵
    Wiltshire, H., B. Wiltshire, A. Citron, T. Clarke, C. Serpe, D. Gray, and W. Herron. 2000. Development of a high-performance liquid chromatographic-mass spectrometric assay for the specific and sensitive quantification of Ro 64-0802, an anti-influenza drug, and its pro-drug, oseltamivir, in human and animal plasma and urine. J. Chromatogr.745:373-388.
    OpenUrlCrossRef
PreviousNext
Back to top
Download PDF
Citation Tools
Lack of Pharmacokinetic Interaction between the Oral Anti-Influenza Prodrug Oseltamivir and Aspirin
Charles Oo, Joanne Barrett, Albert Dorr, Baolian Liu, Penelope Ward
Antimicrobial Agents and Chemotherapy Jun 2002, 46 (6) 1993-1995; DOI: 10.1128/AAC.46.6.1993-1995.2002

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Print

Alerts
Sign In to Email Alerts with your Email Address
Email

Thank you for sharing this Antimicrobial Agents and Chemotherapy article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Lack of Pharmacokinetic Interaction between the Oral Anti-Influenza Prodrug Oseltamivir and Aspirin
(Your Name) has forwarded a page to you from Antimicrobial Agents and Chemotherapy
(Your Name) thought you would be interested in this article in Antimicrobial Agents and Chemotherapy.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Lack of Pharmacokinetic Interaction between the Oral Anti-Influenza Prodrug Oseltamivir and Aspirin
Charles Oo, Joanne Barrett, Albert Dorr, Baolian Liu, Penelope Ward
Antimicrobial Agents and Chemotherapy Jun 2002, 46 (6) 1993-1995; DOI: 10.1128/AAC.46.6.1993-1995.2002
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Top
  • Article
    • ABSTRACT
    • FOOTNOTES
    • REFERENCES
  • Figures & Data
  • Info & Metrics
  • PDF

KEYWORDS

Acetamides
Anti-Inflammatory Agents, Non-Steroidal
antiviral agents
aspirin
Prodrugs

Related Articles

Cited By...

About

  • About AAC
  • Editor in Chief
  • Editorial Board
  • Policies
  • For Reviewers
  • For the Media
  • For Librarians
  • For Advertisers
  • Alerts
  • AAC Podcast
  • RSS
  • FAQ
  • Permissions
  • Journal Announcements

Authors

  • ASM Author Center
  • Submit a Manuscript
  • Article Types
  • Ethics
  • Contact Us

Follow #AACJournal

@ASMicrobiology

       

ASM Journals

ASM journals are the most prominent publications in the field, delivering up-to-date and authoritative coverage of both basic and clinical microbiology.

About ASM | Contact Us | Press Room

 

ASM is a member of

Scientific Society Publisher Alliance

 

American Society for Microbiology
1752 N St. NW
Washington, DC 20036
Phone: (202) 737-3600

Copyright © 2021 American Society for Microbiology | Privacy Policy | Website feedback

Print ISSN: 0066-4804; Online ISSN: 1098-6596