Black Pepper

Black pepper (Piper nigrum) dried fruits, also known as peppercorns, are commonly used as a spice in ground form and are often simply referred to as black pepper.

Black pepper contains a large collection of piperidines, with piperine found in high quantities.

Piperidines Found In Black Pepper Amount
9-(1,3-benzodioxol-5-yl)-1-pyrrolidin-1-ylnon-8-en-1-one Unspecified [1]
Dipiperamide D Unspecified [7]
Dipiperamide E Unspecified [7]
Pipercyclobutanamide A Unspecified [1]
Piperidine 0.5-5% [2]
Piperine 10%
Piptigrine Unspecified [8]
Wisanine Unspecified [8]

Using Black Pepper Medicinally

Piperidine From Black Pepper Tea

To brew a piperidine rich drink from black pepper without extracting much of the piperine, mix course ground black pepper in cold water. Let it steep overnight in the refrigerator. Filter out the solids and discard them. The piperine in the black pepper is very poorly soluble in cold water and most remains in the black pepper grounds.

One 8 ounce cup of tea prepared in this way from 8 grams of black pepper will contain up to 400 mg of piperidine, and up to only 9.4 mg of piperine.

Piperine From Whole Black Pepper

To use black pepper for its piperine content efficiently the black pepper should be consumed whole in capsules, and not brewed as filtered tea.

Doses of up to 8 grams of black pepper have been used orally. However, if brewed as filtered tea, you would need at least 8 1/2 cups of water to hold this level of piperine. Piperine's solubility in water is extremely low (40 mg/L @18 C). 1 cup of water at @18 C can only hold up to 9.4 mg of piperine, the amount of piperine in about 94 mg of black pepper.

Separating Piperidine from Piperine in Black Pepper

Black pepper contains substantial amounts of piperineand piperidine.

Piperine is a very weak base and practically insoluble in water (40 mg/L @ 18 C), and less so in cold water. It does not form salts with weak acids. Piperine hydrochloride is not stable and is practically insoluble in water because it decomposes into hydrochloric acid and piperine on contact with water. Most piperidine salts are very stable, and extremely soluble in water. Piperidine freebase is also highly water soluble..

The boiling point of freebase piperidine (106.3 C) is close to that of water (100 C). In freebase form it distills along with water. It's salt forms boil at much higher temperatures and cannot be distilled along with water. Piperine melts at 130 C and decomposes at higher temperatures. No form of piperine will distill with water.

These highly different characteristics allow these two amines to be easily separated from each other after extraction from black pepper.

Effects on Enzymes and Transporters

Piperine is often wrongfully identified as the active ingredient in black pepper that inhibits CYP2D6. While black pepper inhibits CYP2D6, isolated piperine is a proven selective inhibitor of CYP3A4 with almost no effect on CYP2D6.[6] Other components in black pepper have been identified as potent inhibitors of CYP2D6.[1]

P450 Enzyme Effects Strength Dosage Verified In Humans
CYP1A1 Unspecified Inhibition ? ? ?
CYP2A6 Unspecified Inhibition ? ? ?
CYP2C9 Potent Inhibition ? ? ?
CYP2D6 Potent Inhibition 72.8% inhibition at high doses[3] IC50=315 μg/ml ?
CYP2D6 Potent inhibition from 9-(1,3-benzodioxol-5-yl)-1-pyrrolidin-1-ylnon-8-en-1-one1 >50 % inhibition 10 mM[1] ?
CYP2D6 Potent inhibition from Pipercyclobutanamide A2 >50 % inhibition 10 mM[1] ?
CYP3A4 Potent Inhibition 84.0% Inhibition[3] IC50=29 μg/ml ?
CYP3A4 Potent inhibition from piperine 184% increase in substrates[9] 15 mg for three days[9] Yes[9]
Transporters Effects Strength Dosage Verified In Humans
P-gp Unspecified Inhibition[5] ? ? ?
Aldehyde Dehydrogenase Enzyme Effects Strength Dosage Verified In Humans
Unspecified Unspecified Induction ? ? ?
Aldose Reductase Enzyme Effects Strength Dosage Verified In Humans
hrALR2 Potent Inhibition 0.22 mg/ml[4] ? ?
MAO Enzyme Effects Strength Dosage Verified In Humans
MAO-B Inhibition ? ? ?

1. Mechanism-based inhibition of human liver microsomal cytochrome P450 2D6 (CYP2D6) by alkamides of Piper nigrum.
Subehan, Usia T, Kadota S, Tezuka Y. PubMed PMID: 16808005
2. L. D. Kapoor;
Handbook of Ayurvedic Medicinal Plants, Volume 2 of Herbal Reference Library; CRC Press, 2001; ISBN 0849329299, 9780849329296
3. CYP3A4 and CYP2D6 inhibitory activities of Indonesian medicinal plants.
Usia T, Iwata H, Hiratsuka A, Watabe T, Kadota S, Tezuka Y. PubMed PMID: 16360935
4. Dietary sources of aldose reductase inhibitors: prospects for alleviating diabetic complications.
Saraswat M, Muthenna P, Suryanarayana P, Petrash JM, Reddy GB. PubMed PMID: 19114390
5. Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in
Cancer Chemotherapy Tripta Bansal, Manu Jaggi, Roop K Khar and Sushama Talegaonkar; J Pharm Pharmaceut Sci (www. 12 (1): 46 - 78, 2009 (Download Attached PDF Document)
6. Curcuminoids inhibit multiple human cytochromes P450 (CYP), UDP-glucuronosyltransferase (UGT), and sulfotransferase (SULT) enzymes, while piperine is a relatively selective CYP3A4 inhibitor
Laurie P. Volak, Senait Ghirmai, John R. Cashman, and Michael H. Court PubMed PMC ID: PMC2574793
7. CYP3A4 inhibitory activity of new bisalkaloids, dipiperamides D and E, and cognates from white pepper.
Tsukamoto S, Tomise K, Miyakawa K, Cha BC, Abe T, Hamada T, Hirota H, Ohta T.; Bioorg Med Chem. 2002 Sep;10(9):2981-5.; PMID: 12110320
8. Piptigrine, a new insecticidal amide from Piper nigrum Linn.
Siddiqui BS, Gulzar T, Begum S, Afshan F.; Nat Prod Res. 2004 Oct;18(5):473-7.; PMID: 15248617
9. The effect of piperine on midazolam plasma concentration in healthy volunteers, a research on the CYP3A-involving metabolism
Mohammad Mahdi Rezaee, Sohrab Kazemi, Mohammad Taghi Kazemi, Saeed Gharooee, Elham Yazdani, Hoda Gharooee, Mohammad Reza Shiran and Ali Akbar Moghadamnia; DARU Journal of Pharmaceutical Sciences 2014 22:8; DOI: 10.1186/2008-2231-22-8; PMID: 24398010; PMCID: PMC3904487
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