OCTAVA.- PATENTES, MARCAS Y DERECHOS DE AUTOR.-

Herbs may potentially affect the action of drugs or other herbs when the two are taken concurrently. An herbal product may act as an enhancer or inhibitor of another agent at the site of action. Or it may modify absorption, distribution, metabolism, and/or elimination of that agent.

Little reliable information is available on this topic. A few drug- herb interactions have been documented in human studies or case re- ports, while others have been observed only in animal studies. How- ever, most proposed interactions are based on in vitro assays and speculation about the theoretical mode of action of the herb or its chemical constituents. Knowledge regarding the mode of interaction of the herb is often extrapolated from in vitro studies using individual chemical component(s) of the herb. This logic assumes that the puri- fied, isolated chemical component or components is biologically available and that plasma concentrations reached following con- sumption by a human are commensurate with those used in the study.

Although assumptions about the mode of action of a botanical have provided useful leads in investigations of drug-drug interactions and some drug-herb interactions, they also lead to erroneous conclu- sions. Reports of drug-herb interactions often do not take into consid- eration product differentiation (i.e., garlic powder versus garlic oil). They often do not consider the dose of the herb or the drug, the dura-

tion of treatment, and other critical variables defined for drug-drug interactions, such as the age and genetic profile of the subject. Even so, lists of potential drug-herb interaction are useful as a basis for fur- ther study. Potential interactions have been reviewed in a number of publications (Ernst, 2000; Fugh-Berman, 2000; Brinker, 2001).

Key to many of the drug-herb interactions is the cytochrome P450 family of enzymes. These enzymes are particularly concentrated in the liver but are also present in other tissues, especially the gut. The P450 enzymes metabolize many drugs, essentially clearing them from the body. Many foods and drugs have been found to either stim- ulate or inhibit these enzymes. Stimulation or inhibition of these en- zymes will cause the body to eliminate a drug too quickly or to pre- vent elimination of the drug, thus allowing the drug to build up in the body. These actions are especially a concern with pharmaceuticals whose plasma levels must be tightly controlled to ensure safety and/ or efficacy.

One of the few herbs for which solid human clinical data on herb- drug interactions exist is St. John’s wort. The issue was first raised by an HIV researcher who administered the protease inhibitor indinavir to healthy volunteers in conjuction with St. John’s wort and found that the herb caused indinavir levels to drop to levels below those re- quired for drug efficacy (Piscitelli et al., 2000). Other reports pub- lished around the same time indicated that the same phenomenon might be responsible for acute rejection in organ transplant patients who had used St. John’s wort (Ruschitzka et al., 2000; Barone et al., 2000). Clinical experiments soon revealed that a St. John’s wort prod- uct taken at 300 mg three times daily for 14 days stimulated the activ- ity of a P450 isoenzyme called CYP3A4 (Roby et al., 2000). How- ever, the story may be more complicated, as plasma levels of the anticonvulsant drug carbamazepine, which is also thought to be pri- marily metabolized via CYP3A4, were not affected by the addition of St. John’s wort (Burstein et al., 2000).

Recent attention has also been paid to the effects of herbs on an in- ducible transport system that moves substrates out of cells. The pump, termed P-glycoprotein (Pgp), is a determinant of the oral bioavail- ability of many drugs. Here, too, it has been suggested that St. John’s wort extract increases intestinal expression of Pgp, and, as a result, it is expected that 900 mg extract per day would decrease digoxin con- centrations in heart patients after ten days of use (Durr et al., 2000;

Johne et al., 1999). Digoxin is a cardiac glycoside used in the treat- ment of a number of heart conditions including cardiac insufficiency. This drug is particularly problematic since it has a narrow therapeutic index, meaning that blood levels must be carefully controlled. As with the P450 enzymes, the story with St. John’s wort is complex, as recent clinical experiments have revealed that a St. John’s wort ex- tract with a different chemical profile (low levels of hyperforin), but also clinically effective against depression, was demonstrated not to alter digoxin levels (Brattström, 2002).

The possibility that herbal preparations can affect the delicate bal- ance of patients on anticoagulation agents is another concern. The discovery of the anticoagulant warfarin followed reports of cattle having hemorrhagic disorders following ingestion of sweet clover stored in silos (Vickery and Vickery, 1980; Bruneton, 1999). It was revealed that the hemorrhagic effect was due to the conversion of coumarins present in clover to the anticoagulant, bishydroxycou- marin (dicoumarol), by fungi growing on the clover. This background led numerous authors to pose an anticoagulant alert for any botani- cals that contain coumarins. However, most natural coumarin deriva- tives found in plants do not ordinarily possess anticoagulant activity. Indeed, a few natural coumarins, such as esculetin and osthole, may affect platelet aggregation but do not have a similar mechanism of ac- tion as warfarin (Brinker, 2001). Therefore, the anticoagulant action of plants containing coumarins is not a certainty, as some reference books indicate (Miller and Murray, 1998; Barnes, Anderson, and Phillipson, 2002).

Until we know more about the modes of action of herbal products and their possible interactions with drugs, sensitive populations such as the elderly, chronically ill, and those with compromised immune systems would be well advised to be cautious when combining herbs and drugs.