Coumarin metabolism

Maintenance doses widely vary among patients (e.g., from 1 to 20 mg/day for warfarin), and are influenced by diet (variable vitamin K intake) and medications that affect coumarin metabolism (decreased drug clearance e.g., cotrimoxazole, amiodarone, erythromycin increased clearance e.g., barbiturates, carbamaze-pine, rifampin). Thus, regular monitoring is needed... 

Coronary circulation, 6 (1969) 11 Corticotropin releasing factor receptor antagonists, 41 (2003) 195 Coumarins, metabolism and biological actions, 10 (1974) 85 Cyclic AMP, 12 (1975) 293 Cyclooxygenase-2 (COX-2) inhibitors, 36 (1999) 201... 

Lake B. 1999. Coumarin metabolism, toxicity and carcinogenicity, relevance for human risk assessment. Food Chem Toxicol 37(4) 423-453. 

Coronary circulation, 6 (1969) 11 Coumarins, metabolism and biological actions, 10 (1975) 85... 

Lewis, D. F. and Lake, B. G. (2002) Species differences in coumarin metabolism a molecular modelling evaluation of CYP2A interactions. Xenobiotica 32, 547-561. 

The major pathway of coumarin metabolism in most human subjects is 7-hydroxyl-ation to form 7-hydroxy coumarin, which is excreted in the urine as both glucuronic acid and sulfate conjugates. Coumarin 7-hydroxylation activity exhibits a Gaussian distribution in Caucasian populations (Cholerton et al, 1992 Rautio et al, 1992), but some individuals are deficient in this activity. 

The marked interindividual variation in coumarin metabolism to 7-hydroxy-coumarin has led to studies to evaluate whether a genetic polymorphism exists in human CYP2A6. 

Because of the relative ease of measurement of 7-hydroxycoumarin, many studies have examined this pathway of coumarin metabolism after oral administration. Overall, several species including rats, most mouse strains, Syrian hamsters, guinea-pigs, dogs, marmosets and squirrel monkeys are poor 7-hydroxylators, excreting <5% of the administered dose as urinary 7-hydroxycoumarin (Cohen, 1979 Lake, 1999). 

Apart from glucuronic acid and sulfate conjugation of hydroxycoumarins, other phase II pathways of coumarin metabolism have been identified. For example, ortho-coumaric acid may be conjugated with glycine (Lake, 1999), and a coumarin mercapturic acid conjugate has also been reported (Huwer et al., 1991). Coumarin may also be metabolized by the gastrointestinal microflora to 3,4-dihydrocoumarin and ort/io-hydroxyphenylpropionic acid under anaerobic conditions (Scheline, 1968). 

Lake, B.G (1999) Coumarin metabolism, toxicity and carcinogencity relevance for human risk assessment. Food chem. Toxicol., 37, 423 53 Lake, B.G Evans, J.G (1993) Effect of pretreatment with some mixed-function oxidase enzyme inducers on the acute hepatotoxicity of coumarin in the rat. Food chem. Toxicol., 31, 963-970... 

Keizers PH, Lussenburg BM, de Graaf C, et al. Influence of phenylalanine 120 on cytochrome P450 2D6 catalytic selectivity and regiospecificity crucial role in 7-methoxy-4-(aminomethyl)-coumarin metabolism. Biochem Pharmacol 2004 68 2263-2271. 

Cok I, Kocabas NA, Cholerton S et al. (2001) Determination of coumarin metabolism in Turkish population. Human Exp Pharmacol 20 179-184... 

Inhibition of enteral coumarin absorption by adsorbents, e.g., antacids, medicinal charcoal Inhibition of hepatic coumarin metabolism, e.g., by cimetidine, metronidazole ... 

Murphy, S.E., L.M. Johnson, L.M. Losey S.G. Carmella, and S.S. Hecht (2001). Consumption of watercress fails to alter coumarin metabolism in humans. Drug Metab. Dispos. 29, 786-788. 

Von Weymam, L.B. and S.E. Murphy (2003). CYP2A13-catalysed coumarin metabolism Comparison with CYP2A5 and CYP2A6. Xenobiotica 33, 73-81. 

Clinical uses and toxicity The drug is indicated for severe dermatophytoses of the skin, hair, and nails. Adverse effects include headaches, mental confusion, gastrointestinal irritation, photosensitivity, and changes in liver function. A drug interaction may enhance coumarin metabolism, resulting in decreased anticoagulant effect. 

Cucinell SA, Odessky L, Weiss M, Dayton PG. The effect of chlcral hydrate on bishydroxy-coumarin metabolism. A fetal outcome. J,4A4/i (1966) 197,144-6. 

The two cases of interactions are unexplained. It is not obvious why dividing the acenocoumarol dose, or using ranitidine, would have reversed an interaction. No interaction via inhibition of coumarin metabolism is likely. Sildenafll alone appears to commonly cause nosebleeds in patients with pulmonary hypertension. ... 

No significant changes in coumarin metabolism were observed after several large doses (57 g each) of watercress (Murphy et al. 2001). 

In healthy volunteers orally administered coumarin before or after ingestion of four doses of 56.8 g each of fresh watercress over the course of 24 hours, a marginal inhibitory effect on coumarin metabolism was observed. In approximately 30% of volunteers, a decrease in urinary excretion of coumarin was observed in the first 2 hours after coumarin administration, although the mean excretion of coumarin during that time for all test subjects was not significantly different from the control. Total excretion of the coumarin metabolite was not affected by watercress (Murphy et al. 2001). 

The mild psychostimulants methylpheni-date and prolintane have been held not to interfere with coumarin metabolism or with coumarin-induced hypocoagulability (55 ), contradicting an earlier report (63 ). 

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