Bitter Orange - Guaifenesin, Hydrocodone, Pseudoephedrine Interaction
Herbal: Bitter Orange
Also Known As: Citrus aurantium, Aurantii Fructus, Aurantium, Bigarade, Chisil, Kijitsu, Marmalade Orange, Meta-Synephrine, Naranja Amarga, Neroli Oil, Norsynephrine, Octopamine, Orange Amère, Seville Orange, Shangzhou Zhiqiao, Sour Orange, Synephrine, Zhi Ke, Zhi Qiao, Zhi Shi
Drug: Guaifenesin, Hydrocodone, Pseudoephedrine
Brand names:
Tussi-Organidin DM NR, Entuss-D
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
May 04, 2025
Interaction Details
Guaifenesin, Hydrocodone, Pseudoephedrine is classified as belonging to the following category: Cytochrome P450 2D6 (Cyp2D6) Substrates
Theoretically, bitter orange might increase levels of drug metabolized by CYP2D6.
In vitro research shows that octopamine, a constituent of bitter orange, weakly inhibits CYP2D6 enzymes. This effect has not been reported in humans.
Interaction Rating
Likelihood of Occurrence
PossibleInteraction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists
References
- Liu Y, Santillo MF. Cytochrome P450 2D6 and 3A4 enzyme inhibition by amine stimulants in dietary supplements. Drug Test Anal. 2016;8(3-4):307-10.
Interaction Details
Guaifenesin, Hydrocodone, Pseudoephedrine is classified as belonging to the following category: Cytochrome P450 3A4 (Cyp3A4) Substrates
Bitter orange might increase levels of drugs metabolized by CYP3A4.
Small clinical studies suggest that single or multiple doses of freshly squeezed bitter orange juice 200-240 mL can inhibit CYP3A4 metabolism of drugs, causing increased drug levels and potentially increasing the risk of adverse effects. However, the extent of the effect of bitter orange on CYP3A4-mediated drug interactions is unknown. Some evidence suggests that bitter orange selectively inhibits intestinal CYP3A4, but not hepatic CYP3A4. Its effect on P-glycoprotein, which strongly overlaps with CYP3A4 interactions, is unclear. One small clinical study shows that drinking 8 ounces of freshly squeezed bitter orange juice has no effect on cyclosporine, which seems to be more dependent on hepatic CYP3A4 and P-glycoprotein than intestinal CYP3A4.
Interaction Rating
Likelihood of Occurrence
PossibleInteraction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists
References
- Malhotra S, Bailey DG, Paine MF, Watkins PB. Seville orange juice-felodipine interaction: comparison with dilute grapefruit juice and involvement of furocoumarins. Clin Pharmacol Ther 2001;69:14-23.
- Penzak SR, Acosta EP, Turner M, et al. Effect of Seville orange juice and grapefruit juice on indinavir pharmacokinetics. J Clin Pharmacol 2002;42:1165-70.
- Edwards DJ, Fitzsimmons ME, Schuetz EG, et al. 6',7'-Dihydroxybergamottin in grapefruit juice and Seville orange juice: effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein. Clin Pharmacol Ther 1999;65:237-44.
- Di Marco MP, Edwards DJ, Wainer IW, Ducharme MP. The effect of grapefruit juice and seville orange juice on the pharmacokinetics of dextromethorphan: the role of gut CYP3A and P-glycoprotein. Life Sci 2002;71:1149-60.
- Abdelkawy KS, Donia AM, Turner RB, Elbarbry F. Effects of Lemon and Seville Orange Juices on the Pharmacokinetic Properties of Sildenafil in Healthy Subjects. Drugs R D. 2016 Sep;16(3):271-278.
Interaction Details
Guaifenesin, Hydrocodone, Pseudoephedrine is classified as belonging to the following category: Stimulant Drugs
Theoretically, bitter orange might increase the risk of hypertension and adverse cardiovascular effects when taken with stimulant drugs.
Bitter orange appears to have stimulant effects.
Interaction Rating
Likelihood of Occurrence
PossibleInteraction has been documented in animal or in lab research, or the interaction has been documented in humans but is limited to case reports or conflicting clinical research exists
References
- Penzak SR, Jann MW, Cold JA, et al. Seville (sour) orange juice: synephrine content and cardiovascular effects in normotensive adults. J Clin Pharmacol 2001;41:1059-63.
- Keogh AM, Baron DW. Sympathomimetic abuse and coronary artery spasm. Br Med J 1985;291:940.
Bitter Orange Overview
Bitter orange, also known as Seville orange or sour orange, is a type of citrus fruit that is native to Southeast Asia. It is closely related to the sweet orange, but has a much more bitter and sour flavor.
Bitter orange is a rich source of vitamin C and other nutrients, including calcium, potassium, and folate. It is also a good source of antioxidants.
Bitter orange has been used in traditional medicine for a number of purported health benefits, including improved digestion, improved immune function, and reduced inflammation.
Bitter orange also contains synephrine, a compound similar in structure to ephedrine. Synephrine is thought to have stimulant effects and is often used to increase energy, improve athletic performance, and as a weight loss supplement. When used as a dietary supplement, the dosage is typically standardized by its synephrine content.
Bitter Orange - More Interactions
Bitter Orange interacts with 931 drugs
Interaction Rating Key
These severity listings are for informational use only. Never start, stop or otherwise change your therapy before speaking with your provider.
| Major | The combined use of these agents is strongly discouraged as serious side effects or other negative outcomes could occur. |
| Moderate | Use cautiously under the care of a healthcare professional or avoid this combination. A significant interaction or negative outcome could occur. |
| Minor | Be aware that there is a chance of an interaction. Watch for warning signs of a potential interaction. |
| Unknown | No interactions have been reported or no interaction data is currently available. |
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Parts of this content are provided by the Therapeutic Research Center, LLC.
DISCLAIMER: Currently this does not check for drug-drug interactions. This is not an all-inclusive comprehensive list of potential interactions and is for informational purposes only. Not all interactions are known or well-reported in the scientific literature, and new interactions are continually being reported. Input is needed from a qualified healthcare provider including a pharmacist before starting any therapy. Application of clinical judgment is necessary.
© 2021 Therapeutic Research Center, LLC
Drug descriptions are provided by MedlinePlus.
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In addition to being a clinical pharmacist specializing in pharmacotherapy, Dr. Brian Staiger is a registered herbalist through the American Herbalist Guild. He has combined his passion for pharmacy practice with the study of medical ethnobotany to improve patient care. Feel free to reach out about any of your herbal or medication questions!
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