**7. Interaction with drugs and foods**

The efficacy of the anticoagulant treatment with warfarin highly depends on its bioavailability, since inhibition of the target (epoxy reductase) enzyme depends on direct binding of the drug to this protein [38]. In addition, vitamin K from external sources does not rely on recycling through this enzyme [38]. Hence, the absorption,


**97**

*From Rat Poison to Medicine: Medical Applications of Coumarin Derivatives*

binding sites by the drugs will increase the availability of warfarin.

transport, delivery, and elimination of warfarin as well as the external availability of vitamin K are potential sites of interaction with other drugs and with food and

Drugs and food that influence the enterohepatic circulation can all affect the absorption of warfarin. Examples of these are the drug cholestyramine [37] and the avocado fruit [70], which prevent the reabsorption of warfarin in the intestines Concomitant administration of other protein-bound drugs may lead to greater amounts of circulating warfarin and increased risks of bleeding. Valproate sodium increases the bioavailability of warfarin through dislocation of its protein-binding sites [71]. Interference with the metabolism of warfarin is a potential of most drugs that are eliminated by hepatic metabolism. Among these are aspirin [72], nonsteroidal anti-inflammatory drugs [72], serotonin reuptake inhibitors [49], antiplatelet agents and some antibiotics [72]. It can go both ways with the metabolism. Induction of the cytochromes will increase the elimination, while occupation of the

Since warfarin acts through elimination of available bioactive vitamin K, variations of the net intake of this vitamin will certainly interfere with the drug action. A high intake of the vitamin will keep the coagulant factors at a higher level and thus inhibit the anticoagulant activity. Likewise, a lower intake will potentiate the effect of warfarin. The vitamin occurs in food in the form of phylloquinone and menaquinone. Phylloquinone is the form mostly found in plants and is also the most abundant form in food [73]. Menaquinones are mainly the product of bacterial production or conversion [74]. Consequently, simple multivitamin and other supplements, food with high vitamin K content [74] as well as antibiotics are sources of fluctuation in vitamin K intake since intestinal bacteria significantly contribute to

Recently, another source of interference came into focus. In addition to the previous mentioned parameters, genetic variation in the expression of cytochrome P450 seems to play a role in the metabolism of warfarin [76], thus influencing the availability of the drug [77]. All these considerations make it clear that close monitoring of the individual coagulation ability is necessary for a successful therapy with this agent. The abovementioned interactions are just a few of the many that are possible. **Table 1** gives examples of a variety of interactions with drugs, food, natural products, and supplements. This is only to underscore the cautious approach patients

Today, coumarins find their application predominantly as anticoagulants in medicine. The narrow therapeutic index of warfarin and related compounds sometimes limit their applicability and consequently there is a constant search for more safe agents in this drug class [90]. Unfortunately, the development of these

Aside from these developments, coumarins with several applications in medical practice are progressively being introduced. Investigators found that coumarin-3-carboxylic acid could be utilized as a dosimeter for radiotherapy. This substance converts to the highly fluorescent 7-hydroxy-coumarin-3-carboxylic acid, with a

The coumarin 2-hydroxycinnamic acid demonstrated inhibitive properties on the enzyme carbonic anhydrase [92]. Inhibition of this enzyme leads to diuresis [93] and decreases intraocular pressure in glaucoma patients [93] with clear therapeutic

*DOI: http://dx.doi.org/10.5772/intechopen.89765*

the production of menaquinones [75].

should practice when taking warfarin.

**8. Future prospects and conclusion**

will probably limit the use of these oral anticoagulants.

near perfect linear correlation upon irradiation [91].

potential and clinical perspective.

dietary supplements.

#### **Table 1.**

*Brief overview of possible interactions with warfarin.*

#### *From Rat Poison to Medicine: Medical Applications of Coumarin Derivatives DOI: http://dx.doi.org/10.5772/intechopen.89765*

transport, delivery, and elimination of warfarin as well as the external availability of vitamin K are potential sites of interaction with other drugs and with food and dietary supplements.

Drugs and food that influence the enterohepatic circulation can all affect the absorption of warfarin. Examples of these are the drug cholestyramine [37] and the avocado fruit [70], which prevent the reabsorption of warfarin in the intestines Concomitant administration of other protein-bound drugs may lead to greater amounts of circulating warfarin and increased risks of bleeding. Valproate sodium increases the bioavailability of warfarin through dislocation of its protein-binding sites [71]. Interference with the metabolism of warfarin is a potential of most drugs that are eliminated by hepatic metabolism. Among these are aspirin [72], nonsteroidal anti-inflammatory drugs [72], serotonin reuptake inhibitors [49], antiplatelet agents and some antibiotics [72]. It can go both ways with the metabolism. Induction of the cytochromes will increase the elimination, while occupation of the binding sites by the drugs will increase the availability of warfarin.

Since warfarin acts through elimination of available bioactive vitamin K, variations of the net intake of this vitamin will certainly interfere with the drug action. A high intake of the vitamin will keep the coagulant factors at a higher level and thus inhibit the anticoagulant activity. Likewise, a lower intake will potentiate the effect of warfarin. The vitamin occurs in food in the form of phylloquinone and menaquinone. Phylloquinone is the form mostly found in plants and is also the most abundant form in food [73]. Menaquinones are mainly the product of bacterial production or conversion [74]. Consequently, simple multivitamin and other supplements, food with high vitamin K content [74] as well as antibiotics are sources of fluctuation in vitamin K intake since intestinal bacteria significantly contribute to the production of menaquinones [75].

Recently, another source of interference came into focus. In addition to the previous mentioned parameters, genetic variation in the expression of cytochrome P450 seems to play a role in the metabolism of warfarin [76], thus influencing the availability of the drug [77]. All these considerations make it clear that close monitoring of the individual coagulation ability is necessary for a successful therapy with this agent.

The abovementioned interactions are just a few of the many that are possible. **Table 1** gives examples of a variety of interactions with drugs, food, natural products, and supplements. This is only to underscore the cautious approach patients should practice when taking warfarin.

### **8. Future prospects and conclusion**

Today, coumarins find their application predominantly as anticoagulants in medicine. The narrow therapeutic index of warfarin and related compounds sometimes limit their applicability and consequently there is a constant search for more safe agents in this drug class [90]. Unfortunately, the development of these will probably limit the use of these oral anticoagulants.

Aside from these developments, coumarins with several applications in medical practice are progressively being introduced. Investigators found that coumarin-3-carboxylic acid could be utilized as a dosimeter for radiotherapy. This substance converts to the highly fluorescent 7-hydroxy-coumarin-3-carboxylic acid, with a near perfect linear correlation upon irradiation [91].

The coumarin 2-hydroxycinnamic acid demonstrated inhibitive properties on the enzyme carbonic anhydrase [92]. Inhibition of this enzyme leads to diuresis [93] and decreases intraocular pressure in glaucoma patients [93] with clear therapeutic potential and clinical perspective.

*Phytochemicals in Human Health*

Allopathic medications **Agent Category Possible** 

Amiodarone Antiarrhythmic Inhibition

Ciprofloxacin Antibiotic Reduction

Paroxetine Antidepressant Inhibition

Citalopram Antidepressant Inhibition

medication

medication

Diclofenac NSAID Inhibition

Naproxen NSAID Inhibition

Acetaminophen Analgesic Interference

improvement

improvement

herbal tea

cognitive functions

depression

Antioxidant Interference

Clopidogrel Antiplatelet

Dipyridamole Antiplatelet

Fish oil Lipid profile

Glucosamine Cartilage

Chamomile Medicinal

Ginseng Improving

St John's wort Against

Pomegranate juice

*Brief overview of possible interactions with warfarin.*

**mechanism**

of hepatic metabolism

of vitamin K synthesis by intestinal bacteria

of hepatic metabolism

of hepatic metabolism

Inhibition of coagulation cascade

Inhibition of coagulation cascade

of coagulation cascade

of coagulation cascade

with hepatic metabolism

Inhibition of coagulation cascade?

with hepatic metabolism

Induction of metabolism **Effect Reference**

Increased bleeding

Potentiation [80]

Potentiation [80]

Potentiation [81]

Potentiation [81]

Potentiation [82]

Potentiation [82]

Potentiation [84]

Potentiation [85]

Inhibition [89]

[83]

[87]

Increased bleeding

Unknown Potentiation [86]

bleeding

Unknown Inhibition [88]

Unknown Increased

[78]

[79]

**96**

**Table 1.**

Food supplements

Traditional medications

Furano(pyrano)coumarins found in the roots of the Korean angelica (*Angelica gigas*) showed antibacterial activity in hay bacillus (*Bacillus subtilis*) cultures [94]. The coumarine derivative cloricromene reduced the inflammatory parameters in rats subjected to collagen-induced arthritis [95]. In addition, several studies found that coumarins may be useful as anti-tumor agents [4, 96].

Probably since ancient times, coumarins found their application in medicine. Currently, however, coumarins with predominantly anticoagulant properties are applied in daily medical practice. These have been developed from the initial discovery of a cattle killing weed more than six decades ago. Initially applied as a rodenticide, soon a therapeutic usable oral anticoagulant was developed, and slowly other agents entered the market. They have a small therapeutic index, rendering them toxic in a number of circumstances. The search for more safe agents with anticoagulant effects is ongoing and this may result in a decline of the use of coumarins in this field. Nevertheless, coumarins gradually find their way in other fields of medicine. Nevertheless, all these developments promise a bright future for coumarins in medical applications.
