Dose-related pharmacokinetics of coumarin, 7-hydroxycoumarin and 7-hydroxycoumarin glucuronide upon intraperitoneal administration of coumarin and 7-hydroxycoumarin in the rat.

Blood concentration-time data of coumarin (C), 7-hydroxycoumarin (7-HC) and 7-hydroxycoumarin glucuronide (7-HCG) were obtained in rats receiving intraperitoneal doses of C ranging from 2.5 to 60 mg/kg and of 7-HC ranging from 2.5 to 20 mg/kg. Coumarin blood levels were fit to pharmacokinetic models using computer programs including NONLIN, modified ESTRIP, RESID and AUCRPP. The other molecular species were treated pharmacokinetically by linear least squares regression analysis. C blood concentrations were indicated to be dose-dependent at doses greater than 10 mg/kg. Only trace amounts of 7-HC were found upon C administration, however, 7-HCG was found in measurable quantities at all dose levels. The blood concentration-time data of 7-HC and 7-HCG were very erratic with considerable intersubject variation. 7-HC levels upon 7-HC dosing were found to have extremely short half-lives of elimination for all animals tested. Deviation from linearity was apparent at the 20 mg/kg dose for 7-HC. The 7-HCG metabolite upon 7-HC dosing also showed dose-dependent kinetics at the 20 mg/kg dose. 7-HCG was found to appear at variable rates in the blood with peak times ranging from about 2 to 50 min.