User login
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.
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).
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.
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 anti-inflammatory, 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.
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’-diphospho-glucuronosyltransferase 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.
Related Resources
1. Natural Medicines Database. Garlic monograph. http://naturaldatabase.therapeuticresearch.com. Accessed May 1, 2017.
2. Wanwimolruk S, Prachayasittikul V. Cytochrome P450 enzyme mediated herbal drug interactions (part 1). EXCLI 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, Gardner SF, Hubbard MA, et al. 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. Phytother Res. 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.
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.
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).
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.
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 anti-inflammatory, 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.
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’-diphospho-glucuronosyltransferase 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.
Related Resources
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.
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).
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.
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 anti-inflammatory, 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.
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’-diphospho-glucuronosyltransferase 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.
Related Resources
1. Natural Medicines Database. Garlic monograph. http://naturaldatabase.therapeuticresearch.com. Accessed May 1, 2017.
2. Wanwimolruk S, Prachayasittikul V. Cytochrome P450 enzyme mediated herbal drug interactions (part 1). EXCLI 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, Gardner SF, Hubbard MA, et al. 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. Phytother Res. 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.
1. Natural Medicines Database. Garlic monograph. http://naturaldatabase.therapeuticresearch.com. Accessed May 1, 2017.
2. Wanwimolruk S, Prachayasittikul V. Cytochrome P450 enzyme mediated herbal drug interactions (part 1). EXCLI 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, Gardner SF, Hubbard MA, et al. 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. Phytother Res. 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.
