Pharmacokinetics of coumarin and its 7-hydroxy-metabolites upon intravenous and peroral administration of coumarin in man

Abstract

The pharmacokinetics of coumarin (C) upon i.v. and p.o. administration and its metabolites 7-hydroxy-coumarin (7-HC) and 7-hydroxy-coumarin glucuronide (7-HCG) have been studied. Six healthy volunteers were involved in this investigation. Four of the volunteers participated in a crossover study. Coumarin was administered i.v. and p.o. in dose sizes of 0.25 mg/kg and 0.857 mg/kg, respectively. Coumarin is rapidly absorbed p.o., however the availability to systemic circulation is less than 4%. The rest of the dose appears quantitatively as 7-HC and 7-HCG in systemic circulation suggesting an extensive firstpass effect. Coumarin and 7-HCG are best fitted to an open two-compartment model, whereas 7-HC is best fitted to an open one-compartment model. The biological half-life of both C (0.80 vs. 1.02 h) and 7-HCG (1.47 vs. 1.15 h) was not significantly different for the two routes of administration. The large total clearance of C again suggests a first-pass effect; while that of 7-HCG, which is nearly exclusively eliminated into urine, indicates active tubular secretion of the glucuronide.

Chromatographical profiles of fluid extracts and tinctures obtained from Mikania glomerata Sprengel sterilized by gamma ray irradiation

“…Coumarins are lactones which can be easily opened upon treatment with alkali into cis-o-hydroxycinnamic acids. Coumarin itself is devoid of anticoagulant properties (Ritschell, 1977;O'Riley, 1980) but if coumarin containing plants are not properly stocked, the compound can be metabolized by certain fungi (Penicillium nigricans or P. jensi) into dicumarol, a 4-hydroxycoumarin derivative with very potent anticoagulant activity (De Smet, 1992). One classic example is the "Sweet Clover Disease", an hemorrhagic condition described for the plant Melilotus offi cinalis, a coumarin containing medicinal plant (De Smet, 1992).…”

CYP2A6 Genotype, Phenotype, and the Use of Nicotine Metabolites as Biomarkers during Ad libitum Smoking

“…A plasma or urine sample is collected at a specific time; the parent drug and the metabolite levels are assessed; and the metabolite ratio calculated providing an index of their in vivo phenotype (26,27). Coumarin 7-hydroxylation is mediated by CYP2A6; whereas coumarin could be used in smokers, it is a poor probe drug as it is highly extracted (28), limiting its use to distinguish intermediate, normal, and fast CYP2A6 activity. In addition, some CYP2A6 genetic variants alter coumarin metabolism differently than nicotine metabolism, and smokers have reduced rates of metabolism.…”

Transport of the Coumarin Metabolite 7-Hydroxycoumarin Glucuronide Is Mediated via Multidrug Resistance-Associated Proteins 3 and 4

“…The clearance of 7-HC-G exceeds the glomerular filtration rate; therefore, it is considered to be actively secreted into the urine by the tubular segments in the kidney (Ritschel et al, 1977). Efflux transporters belonging to the ATP-binding cassette family, such as multidrug-resistance associated proteins (MRPs), breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp) are known to play a role in the active tubular secretion of compounds from the kidney (Schinkel and Jonker, 2003;El-Sheikh et al, 2008).…”

“…In addition, 7-HC is used as a model substrate for the investigation of glucuronidation activity of liver and intestinal models because many UGTs have the capability to glucuronidate this compound (De Kanter et al, 2002;Brown et al, 2003;van de Kerkhof et al, 2006) (Fig. 1). 7-HC-G represents the main metabolite in plasma, indicating that it is formed in intestine or liver, and at a low dose of coumarin, approximately 80 to 90% of the absorbed dose of coumarin is excreted in urine, mainly as 7-HC-G, whereas Ͻ1% is excreted via the feces (Shilling et al, 1969;Ritschel et al, 1977;Ford et al, 2001). At higher doses of coumarin, the metabolism seems to become saturated, which is reflected in a lower percentage of 7-HC and 7-HC-G excretion in urine (55-63%) (Egan et al, 1990;Asimus et al, 2008).…”

“…1). 7-HC-G represents the main metabolite in plasma, indicating that it is formed in intestine or liver, and at a low dose of coumarin, approximately 80 to 90% of the absorbed dose of coumarin is excreted in urine, mainly as 7-HC-G, whereas Ͻ1% is excreted via the feces (Shilling et al, 1969;Ritschel et al, 1977;Ford et al, 2001). At higher doses of coumarin, the metabolism seems to become saturated, which is reflected in a lower percentage of 7-HC and 7-HC-G excretion in urine (55-63%) (Egan et al, 1990;Asimus et al, 2008).The clearance of 7-HC-G exceeds the glomerular filtration rate; therefore, it is considered to be actively secreted into the urine by the tubular segments in the kidney (Ritschel et al, 1977). Efflux transporters belonging to the ATP-binding cassette family, such as multidrug-resistance associated proteins (MRPs), breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp) are known to play a role in the active tubular secretion of compounds from the kidney (Schinkel and Jonker, 2003;El-Sheikh et al, 2008).…”