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Herb-drug interactions: caution patients when changing supplements.

Ms. X, age 41, has a history of bipolar disorder and presents with extreme sleepiness, constipation with mild abdominal cramping, occasional dizziness, and "palpitations." Although usually she is quite articulate, Ms. X seems to have trouble describing her symptoms and reports that they have been worsening over 4 to 6 days. She is worried because she is making mistakes at work and repeatedly misunderstanding directions.

Ms. X has a family history of hyperlipidemia, heart disease, and diabetes, and she has been employing a healthy diet, exercise, and use of supplements for cardiovascular health since her early 20s. Her medication regimen includes lithium, 600 mg, twice a day, quetiapine, 1,200 mg/d, a multivitamin and mineral tablet once a day, a brand name garlic supplement (garlic powder, 300 mg, vitamin C, 80 mg, vitamin E, 20 IU, vitamin A, 2,640 IU) twice a day, and fish oil, 2 g/d, at bedtime. Lithium levels consistently have been 0.8 to 0.9 mEq/L for the last 3 years.

Ms. X describes no changes in her diet or prescription medications, but mentions that the brand name garlic supplement she takes was out of stock early last week, so she bought another brand of garlic supplement, consisting of oil capsules. Ms. X says, "I made sure the dose was exactly the same, since you told me not to change doses without check ing with you first!" You review the bottle she brought with her and see that it contains garlic oil with "allien equivalent to 300 mg of garlic powder" and 60 mg of vitamin C with rose hips, vitamin E, 20 IU, vitamin A, 2,200 IU, and piperine, 20 mg.

Factors of drug-supplement interactions

Because an interaction is possible doesn't always mean that a drug and an offending botanical cannot be used together. With awareness and planning, possible interactions can be safely managed (Table 1). Such was the case of Ms. X, who was stable on a higher-than-usual dosage of quetiapine (average target is 600 mg/d for bipolar disorder) because of presumed moderate enzyme induction by the brand name garlic supplement. Ms. X did not want to stop taking this supplement when she started quetiapine. Although garlic is listed as a possible moderate cytochrome P450 (CYP) 3A4 inducer, there is conflicting evidence. (1) Ms. X's clinician advised her to avoid changes in dosage, because it could affect her quetiapine levels. However, the change in the botanical preparation from dried, powdered garlic to garlic oil likely removed the CYP3A4 enzyme induction, leading to a lower rate of metabolism and accumulation of the drug to toxic levels.

Drug metabolism. Practitioners are increasingly aware that St. John's wort can significantly affect concomitantly administered drug levels by induction of the CYP isoenzyme 3A4 and more resources are listing this same possible induction for garlic. (1) However, what is less understood is the extent to which different preparations of the same plant possess different chemical profiles (Table 2, page 40).

Clinical studies with different garlic preparations--dried powder, aqueous extracts, deodorized preparations, oils--have demonstrated diverse and highly variable results in tests of effects on CYP isoenzymes and other metabolism activities. (2) There also is contradictory evidence between in vitro and in vivo studies, with 1 in vitro study of garlic extract demonstrating marked CYP3A4 effects up to 30%, while another study using a water-soluble, aged garlic extract noted little or no effects. (3)
Box
The function of P-glycoprotein

P-glycoprotein is known as a multi-drug
resistance protein because it is involved in
resistance mechanisms for a number of drugs.
P-glycoprotein is involved in drug transport in
the gut where it functions as an efflux pump,
sending toxins and other xenobiotics, such
as drugs, back into the intestinal lumen. It
functions similarly as a component of the
blood-brain barrier. When P-glycoprotein is
inhibited, bioavailability of orally administered
drugs goes up and penetration across the
blood-brain barrier increases; inducement of
P-glycoprotein results in lower blood levels of
the target drug.


Other studies also have demonstrated opposite results. (2) A clinical trial in healthy participants found no difference in the pharmacokinetic parameters of the CYP3A4 substrate drug midazolam before and after administration of a garlic oil supplement. (4) However, inhibition of CYP2E1 was likely, demonstrated by a 22% increase in levels of the skeletal muscle relaxant chlorzoxazone. (4) A study of garlic on ritonavir pharmacokinetics demonstrated large intra-subject variations, leading researchers to speculate that the garlic extract used could be both inducing and inhibiting CYP3A4, as well as having effects on drug absorption via P-glycoprotein (Box, page 39). This brings up another possible interaction because Ms. X substituted a different brand and form of garlic. (5)

Drug absorption. Small differences in amounts of vitamins in the supplement are unlikely to be clinically significant, but the addition of piperine could be affecting quetiapine absorption. Piperine, a constituent of black pepper and long pepper, is used in Ayurvedic medicine for:

* pain

* influenza

* rheumatoid arthritis

* asthma

* loss of appetite

* stimulating peristalsis. (6)

Animal studies have demonstrated antiinflammatory, anticonvulsant, anticarcinogenic, and antioxidant effects, as well as stimulation of digestion via digestive enzyme secretion and increased gastromotility. (3,6)

Because piperine is known to increase intestinal absorption by various mechanisms, it often is added to botanical medicines to increase bioavailability of active components. BioPerine is a 95% piperine extract marketed to be included in vitamin and herbal supplements for that purpose. (3) This allows use of lower dosages to achieve outcomes, which, for expensive botanicals, could be a cost savings for the manufacturer. Studies examining piperine's influence on drug absorption have demonstrated significant increases in carbamazepine, rifampin, phenytoin, nevirapine, and many other drugs. (7,8) These increases are caused by several mechanisms, but the 2 most important may be inhibition of intestinal P-glycoprotein and increases in small intestine absorption surfaces (Table 2). (6-9)

In addition to increased absorption, piperine seems to be a non-specific general inhibitor of CYP isoenzymes; IV phenytoin levels also were higher among test participants. (6,8) Piperine reduces intestinal glucuronidation via uridine 5'-diphosphoglucuronosyltransferase inhibition, and the small or moderate effects on lithium levels seem to be the result of diuretic activities. (3,7) Patients often are motivated to control at least 1 aspect of their medical treatment, such as the supplements they choose to take. Being open to patient use of non-harmful or low-risk supplements, even when they are unlikely to have any medicinal benefit, helps preserve a relationship in which patients are more likely to consider your recommendation to avoid a harmful or high-risk supplement.

Clinical Point

Piperine has been shown to increase small intestine absorption surfaces and inhibit intestinal P-glycoprotein

Practice Points

* Severity of herb-drug interactions range from inconsequential to life-threatening.

Compared with prescription drugs, there is less research on the effects of supplements on metabolism enzymes and absorption processes.

* Differences in product quality and ingredients can create interactions or other safety concerns when changing brands or product formulations.

* Many statements and cautions about herb-drug interactions in tertiary resources are based on in vitro results; therefore, check citations and consult several sources before making a clinical decision.

* Individual genetic differences can result in unpredictable effects. Use caution when interpreting or extrapolating case reports or human studies.

Clinical Point

Because an interaction is possible doesn't mean that a drug and an offending botanical cannot be used together

Clinical Point

Different garlic preparations have shown diverse and highly variable results of the effects of CYP isoenzymes and metabolism

Clinical Point

Piperine has been shown to increase small intestine absorption surfaces and inhibit intestinal P-glycoprotein

Related Resources

* Pasi AK. Herb-drug interaction: an overview. Intl J Pharmaceut Sci Res. 2013;4(10):3770-3774.

* Hermann R, von Richter 0. Clinical evidence of herbal drugs as perpetrators of pharmacokinetic drug interactions. Planta Med. 2012;78(13):1458-1477.

* Natural Medicines Database, www.naturalmedicines. therapeuticresearch.com.

* Lexi-Natural Products. http://webstore.lexi.com/Store/ Individual-Databases/Lexi-Natural-Products.

* National Center for Complementary and Integrative Health. Herbs at a Glance, https://nccih.nih.gov/health/ herbsataglance.htm.

Drug Brand Names

Carbamazepine * Tegretol, Carbatrol Chlorzoxazone * Lorzone, Parafon Lithium * Eskalith, Lithobid Midazolam * Versed Nevirapine * Viramune Phenytoin * Dilantin Quetiapine * Seroquel Rifampin * Rifadin Ritonavir * Norvir

Cydney E. McQueen, PharmD

Vicki L. Ellingrod, PharmD, FCCP Department Editor

Dr. McQueen is Clinical Associate Professor, Pharmacy Practice and Administration, University of Missouri-Kansas City, School of Pharmacy, Kansas City, Missouri.

Disclosure

The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

References

(1.) Natural Medicines Database. Garlic monograph, http:// naturaldatabase.therapeuticresearch.com. Accessed May 1, 2017.

(2.) Wanwimolnik S, Prachayasittikul V. Cytochrome P450 enzyme mediated herbal drug interactions (part 1). EXCU J. 2014;13:347-391.

(3.) Colalto C. Herbal interactions on absorption of drugs: mechanism of action and clinical risk assessment. Pharmacol Res.2010;62(3):207-227.

(4.) Gurley BJ, GardnerSF, Hubbard MA, etal. Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St. John's wort, garlic oil, Panax ginseng and Ginkgo biloba. Drugs Aging. 2005;22(6):525-539.

(5.) Gallicano K, Foster B, Choudhri S. Effect of short-term administration of garlic supplements on single-dose ritonavir pharmacokinetics in healthy volunteers. Br J Clin Pharmacol. 2003;55(2):199-202.

(6.) Meghwal M, Goswami TK. Piper nigrum and piperine: an update. PhytotherRes. 2013;27(8):1121-1130.

(7.) Natural Medicines Database. Black pepper monograph. https://www.naturalmedicines.therapeuticresearch.com. Accessed May 1, 2017.

(8.) Zhou S, Lim LY, Chowbay B. Herbal modulation of p-glycoprotein. Drug Metab Rev. 2004;36(1):57-104.

(9.) Chinta G, Syed B, Coumar MS, et al. Piperine: a comprehensive review of pre-clinical and clinical investigations. Curr Bioact Compd. 2015;11(3):156-169.
Table 1
Strategies for decreasing the risk of herb-drug interactions

Take a complete and accurate medication history by asking patients
about their use of vitamins and herbs in an open and accepting
manner

Obtain brand names and exact lists of ingredients and dosages. Ask
patients to bring supplement containers, if possible

Check for interaction information from multiple sources; verify
with recent primary literature when possible:

* "No interactions known" does not mean that no interactions exist

* Many herb-drug interactions listings primarily focus on the more
well-known cytochrome P450 enzymes-associated interactions

Educate patients to avoid sudden changes in supplements--stopping,
starting, or switching brands Stability is not guaranteed;
manufacturers may change ingredients or quality at any time

Educate patients to watch for symptoms that would indicate a
possible developing interaction

Table 2
Clinical factors to consider with herb--drug interactions

Effect             Causes                 Examples

Changes in drug    Physical               Psyllium, flax seed,
absorption         interference with      marsh mallow, chitosan
                   drug by blocking
                   or binding

                   Inhibition of          Piperine, ginkgo,
                   intestinal             milk thistle, ginseng
                   P-glycoprotein

                   Increases in           Aloe, cascara sagrada,
                   intestinal motility    European buckthorn
                   or diarrhea

Increased free     Displacement of        Willow, meadowsweet
drug levels        protein-bound drugs

Pharmacokinetic    Inhibition or          St. John's wort,
changes            induction of           echinacea, ginkgo,
                   cytochrome P450        garlic, grapefruit,
                   enzymes                goldenseal, resveratrol

Changes in         Increased diuresis     Dandelion, yerba mate,
elimination        or fluid retention     stinging nettle, cowhage

Pharmacodynamic    Supplement has         Anticonvulsants: ginkgo
interactions       either similar or      (may lower seizure
                   opposing effects       threshold)
                   to target drug
                                          Antihypertensives: yohimbe
                                          (could increase blood
                                          pressure)

                                          CNS depressants: valerian
                                          (GABA agonist)
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Title Annotation:Savvy Psychopharmacology
Author:McQueen, Cydney E.
Publication:Current Psychiatry
Geographic Code:1USA
Date:Jun 1, 2017
Words:1852
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