Which medications used in paediatric practice have demonstrated natural health product-drug interactions?

A recent Canadian survey (1) of 1804 children and youth suggested that 49% had tried one or more complementary and alternative medicine therapies and 41% had used a natural health product (NHP) in the previous year. Similarly, a three-month survey (2) of 142 families in an American paediatric emergency department suggested that 45% of caregivers had given their children an herbal remedy in the previous year.

NHP use may be much higher within certain subgroups of the child and youth population (eg, children with serious and/or chronic conditions, such as cancer, cystic fibrosis, asthma, attention deficit hyperactivity disorder and eating disorders) (3–7). In particular, NHP use may be highest in paediatric populations with chronic disease who suffer relapses or other setbacks (3). Surveys have also shown that rates of NHP use are high (70%) among homeless youth, many of whom suffer from chronic mental and physical health conditions (8). Indeed, because children with serious, chronic or recurrent illnesses are the most likely to be on concurrent prescription medications, they may have the highest risk for clinically relevant NHP-drug interactions.

With expanding use, clinicians and researchers are focusing their attention on the potential for NHPs to interact with prescribed medications and alter their pharmacokinetics. Pharmacokinetics involves the study of the rate of movement of drugs within biological systems, as affected by absorption, distribution, metabolism and elimination from the body. Although the mechanisms of NHP-drug interactions are complex and not fully elucidated, interactions are primarily due to altered biotransformation; in particular, herbs may cause induction (or inhibition) of the hepatic cytochrome P450 (CYP) isozymes, rendering the index drug less (or more) active (Figure 1) (9). The CYP isozyme families most commonly involved in human liver metabolism are 1A, 2B, 2C, 2D, 2E and 3A. Many prescription drugs are metabolized through the CYP system, namely the CYP3A4 isoform (9). For example, St John’s wort and garlic are metabolized through the 3A4 isoform and appear to induce other CYP isozymes (9). A recent overview (10) of pharmacokinetic clinical investigations of NHP-drug interactions found that no such clinical investigations have been conducted in children. The search included major electronic databases (CENTRAL, MEDLINE, EMBASE and AMED) from inception to August 2004. Studies investigating pharmacokinetic interactions between an NHP and the metabolism of a regulated medication were included. In an attempt to determine the relevance of potential NHP-drug interactions to the paediatric population, commonly used reference texts were used to identify drugs used in paediatric practice (eg, Pediatric Dosage Handbook [11] and The Harriet Lane Handbook: A Manual for Pediatric House Officers, 16th Edition [12]). Forty-four adult trials examining drug interactions with 11 different common herbal preparations and 11 traditional preparations were identified. Significant NHP-drug interactions were demonstrated in 18 studies among five common herbal remedies with 13 drugs prescribed in paediatric practice. In 18 studies, there was a decreased area under the curve (AUC) or concentration maximum (C_max), and, thus, decreased systemic bioavailability of the probe drug. Significant decreases in the AUC were demonstrated in trials with warfarin (when administered with American ginseng) (13), midazolam (with echinacea) (14), saquinavir (with garlic) (15) and alprazolam (with ginkgo biloba) (16). In addition, St John’s wort significantly decreased the AUC or C_max when administered with alprazolam (AUC [17,18]), amitriptyline (AUC [19]), cyclosporin A (AUC [20]), digoxin (AUC [21,22]), fexofenadine (AUC and C_max [23]), indinavir (AUC [24]), midazolam (AUC and C_max [23]), omeprazole (AUC [25]), oral contraceptive (3-ketodesogestrel) (AUC [26]), simvastatin (AUC [27]), tacrolimus (AUC [28,29]) and warfarin (AUC [30]) (Table 1).

Figure 1.

Sequential first-pass elimination of a theoretical drug through metabolism by the cytochrome P450 isoenzyme CYP3A4 and/or transport by P-glycoprotein (P-gp) in enterocytes of the small intestine and then hepatocytes of the liver. The percentage of the initial drug dose that is available before and after passage through the gut wall and liver is presented. Although the drug is 100% absorbed from the gastrointestinal tract, its bioavailability is only 15% after oral administration. Reprinted with permission from reference 31

TABLE 1.

Summary of significant paediatric herb-drug interactions

Pharmacokinetic trial	Herb	Drug used in paediatric practice
Yuan et al, 2004 (13)	American ginseng	Warfarin
Gorski et al, 2004 (14)	Echinacea	Midazolam
Piscitelli et al, 2002 (15)	Garlic	Saquinavir
Markowitz et al, 2003 (16)	Ginkgo biloba	Alprazolam
Markowitz et al, 2000 (17)	St John’s wort	Alprazolam
Markowitz et al, 2003 (18)	St John’s wort	Alprazolam
Johne et al, 2002 (19)	St John’s wort	Amitriptyline
Bauer et al, 2003 (20)	St John’s wort	Cyclosporin A
Johne et al, 1999 (21)	St John’s wort	Digoxin
Mueller et al, 2004 (22)	St John’s wort	Digoxin
Dresser et al, 2003 (23)	St John’s wort	Fexofenadine
Piscitelli et al, 2000 (24)	St John’s wort	Indinavir
Wang et al, 2004 (25)	St John’s wort	Omeprazole
Pfrunder et al, 2003 (26)	St John’s wort	Oral contraceptive
Sugimoto et al, 2001 (27)	St John’s wort	Simvastatin
Mai et al, 2003 (28)	St John’s wort	Tacrolimus
Hebert et al, 2004 (29)	St John’s wort	Tacrolimus
Jiang et al, 2004 (30)	St John’s wort	Warfarin

St John’s wort has been studied most extensively, and the mechanism for NHP-drug interaction is best understood using this example. The strength and consistency of St John’s wort’s effect on reducing drug bioavailability suggests that it often has important effects in reducing systemic exposure of a variety of drugs. Whether patients take a conventional medication for a condition that is unrelated to the illness for which the patient is using a NHP (eg, fexofenadine for allergic rhinitis and St John’s wort for depression) or they use two interacting compounds for the same illness (eg, amitriptyline and St John’s wort), patients should be closely monitored for a lack of clinical response to standard dosing or an unexpected adverse event that could be due to undisclosed use or discontinuation of NHPs (9). St John’s wort, along with garlic, American ginseng, ginkgo and echinacea should be avoided in children and youth taking medications that have demonstrated significant herb-drug interactions. The degree to which decreases in the AUC or C_max result in clinically relevant drug interactions will depend on the therapeutic index of the specific probe drugs and their minimum effective concentrations.