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First-pass effect of coumarin in man
International Journal of Clinical Pharmacology and Biopharmacy
|March 1, 1979
Summary
Coumarin is fully absorbed but undergoes extensive first-pass effect, with only 2-6% of the parent drug reaching circulation intact. This suggests coumarin acts as a prodrug, with 7-hydroxycoumarin being the active form.
Area of Science:
- Pharmacokinetics
- Drug Metabolism
- Bioavailability Studies
Background:
- Coumarin administration via intravenous (i.v.) and oral (p.o.) routes was studied.
- Analysis focused on extent of bioavailability (EBA) and first-pass effect (FPE).
Purpose of the Study:
- To quantify the bioavailability and first-pass metabolism of coumarin.
- To determine the fraction of unchanged coumarin reaching systemic circulation.
Main Methods:
- Cross-over study design.
- Analysis of blood levels over time for coumarin (C) and its metabolite 7-hydroxycoumarin (7HC).
- Calculation of area under the curve (AUC) for i.v. and p.o. administration.
Main Results:
- All administered coumarin was absorbed, but only 2-6% of intact coumarin reached systemic circulation.
- Extensive first-pass effect was observed, with the fraction of unchanged drug (fFPE) varying from 2.5% to 13% after correction for individual liver blood flow.
- 7-hydroxycoumarin was identified as the main metabolite.
Conclusions:
- Coumarin exhibits a significant first-pass effect, indicating extensive metabolism.
- The findings suggest coumarin may function as a prodrug, with 7-hydroxycoumarin being the pharmacologically active moiety.
- Further research is needed to elucidate the precise sites of first-pass metabolism (liver vs. intestinal).