First-pass effect of coumarin in man.

Blood level versus time data upon i.v. and p.o. administration of coumarin in a cross-over study have been analyzed for extent of bioavailability (EBA) and first-pass effect (FPE). In whole blood the parent drug, coumarin (C), and its main metabolite, 7-hydroxycoumarin (7HC), after hydrolysis of the glucuronide were determined. Comparison of the areas under the curve (AUCO leads to infinity) for C and 7HC upon i.v. and p.o. administration revealed that all of the drug is absorbed; however, only approximately 2-6% of C reaches systemic circulation in intact form. Hence, extensive first-pass effect must be assumed. The fraction of unchanged drug reaching systemic circulation predicted from the i.v. study fFPE varied between 0 and 38% assuming a liver blood flow rate (LBF) of 1.53 1/min. When corrected for individual LBF the fPFE varied between 2.5 and 13%. The question whether the FPE is only due to metabolism in the liver or in part due to biotransformation in the intestinal lumen, gut wall and/or portal blood will be the subject of a further paper. It is suspected that C is the pro-drug and 7HC the pharmacologic active moiety.