Pepper

• Synonym(s) and related species Black and white pepper are derived from the fruits of the same species, Piper nigrum L.

• Black pepper is the unripe fruit which has been immersed in hot water and dried in the sun, during which the outer pericarp shrinks and darkens into a thin, wrinkled black layer.

• White pepper consists of the seed only, prepared by soaking the fully ripe berries, removing the pericarp and drying the naked seed.

• Long pepper, Piper longum L., is a closely related species where the fruits are smaller and occur embedded in flower ‘spikes’, which form the seed heads.

Constituents

• Alkaloids and alkylamides, the most important being

  • • • Piperine, with piperanine,

      • Piperettine, piperlongumine,

      • Pipernonaline, lignans

• Minor constituents such as the piperoleins, have been isolated from the fruits of both species of pepper.

• Black pepper and long pepper also contain a volatile oil which may differ in constitution, but is composed of bisabolene, sabinene and many others; white pepper contains very little.

• The pungent taste of pepper is principally due to piperine, which acts at the vanilloid receptor.

Use and indications

• Pepper is one of the most popular spices in the world, and it is also used as a folk medicine in many countries.

• It is used as a stimulant and carminative, and is reputed to have anti-asthmatic, anti-oxidant, antimicrobial, hepatoprotective and hypocholesterolaemic effects.

• Most of the pharmacological effects reported to date are attributed to piperine. A black pepper extract containing 95% piperine is used in a number of herbal supplements.

• Both long pepper and black pepper are important ingredients of many Ayurvedic herbal medicines where they are intended to enhance absorption of other medicines, for example in the traditional formula known as Trikatu, which contains Piper nigrum, Piper longum and Zingiber officinale in a ratio of 1:1:1. There is increasing evidence to support this rationale as well as some of the other traditional uses, but it should be noted that the actions of Trikatu are not always the same as for pepper extracts or pure piperine, and Trikatu has been implicated in reducing rather than enhancing bioavailability of some drugs. Trikatu is also used as a digestive aid.

Pepper + Barbiturates

Mechanism

It was suggested that the increase in sleeping time induced by pentobarbital and phenobarbital was a result of inhibition of drug metabolising enzymes by piperine.

Pepper + Beta-lactam antibacterials

Mechanism

• The increase in elimination half-life of amoxicillin and cefotaxime suggests a mechanism affecting drug clearance, and not a mechanism of increased gastrointestinal absorption.

• Although the effect on drug metabolising enzymes cannot be ruled out, this is unlikely as none of these antibacterials undergoes significant metabolism by this route.

Pepper + Digoxin

In two in vitro studies, piperine inhibited the transport of digoxin by P-glycoprotein in a concentration-dependent manner. In one of these studies, piperine 50 micromol had an effect comparable to verapamil 100 micromol, a known P-glycoprotein inhibitor.

Turmeric + Herbal medicines; Pepper

Piperine, a major constituent of pepper, increases the bioavailability of curcumin, a major constituent of turmeric.

Mechanism

Unknown It was suggested that piperine may inhibit the metabolism of curcumin.

Pepper + Isoniazid

Mechanism

It has been suggested that Trikatu delays gastric motility, causing retention of the isoniazid in the stomach. Since isoniazid is largely absorbed from the intestine, this might explain the decrease in plasma isoniazid concentrations

Pepper (Piper nigrum) may modestly increase the levels of coenzyme Q10.

Mechanism

It was suggested that piperine increased the absorption of coenzyme Q10 from the gastrointestinal tract, but the exact mechanism is unclear.

Pepper + NSAIDs

It was expected that Trikatu might increase the bioavailability of diclofenac and indometacin. It is possible that there was an incompatibility between diclofenac and a constituent of Trikatu in the single suspension that resulted in the decreased absorption. The increased bioavailability of oxyphenbutazone with piperine was attributed to increased gastric absorption and inhibition of hepatic metabolism of oxyphenbutazone.

Pepper + Nevirapine

Piperine markedly increases the AUC of a single dose of nevirapine in healthy subjects

Mechanism

Uncertain. It was suggested that piperine inhibited the cytochrome P450 isoenzyme CYP3A4, which is involved in the metabolism of nevirapine. However, since the elimination half-life of nevirapine was unaltered, it is unlikely that hepatic CYP3A4 was affected. Also, inhibition of gastrointestinal CYP3A4 would not explain the marked increase in nevirapine levels seen, because nevirapine is already over 90% bioavailable. On repeated dosing nevirapine induces its own metabolism

Pepper + Phenytoin

Piperine appears to increase the maximum levels and AUC of phenytoin, although the effect may be less in patients receiving long-term phenytoin.

Mechanism

The increase in bioavailability of phenytoin caused by piperine may be the result of increased gastrointestinal absorption and decreased elimination. The effects of piperine in patients already taking phenytoin were far less marked than those in the healthy subjects given single doses of phenytoin. This might be because a single dose of piperine was given simultaneously with the phenytoin in the study in patients, rather than prior to the phenytoin. Alternatively, it could be that, after long-term use of phenytoin, piperine has little effect on the elimination of phenytoin.

Pepper + Theophylline

Piperine almost doubled the AUC of a single dose of theophylline.

Mechanism

Piperine is known to increase the absorption of some substances from the gastrointestinal tract, but the exact mechanism is unclear. However, theophylline already has high oral bioavailability. The finding of an increased elimination half-life suggests a mechanism of reduced metabolism or clearance. Piperine is known to inhibit some of the cytochrome P450 isoenzymes, although there do not appear to be any data specifically on CYP1A2, which is mainly involved in the metabolism of theophylline

References

1. Mujumdar AM, Dhuley JN, Deshmukh VK, Raman PH, Thorat SL, Naik SR. Effect of piperine on pentobarbitone induced hypnosis in rats. Indian J Exp Biol (1990) 28, 483

2. Kasibhatta R, Naidu MUR. Influence of piperine on the pharmacokinetics of nevirapine under fasting conditions: a randomised, crossover, placebo-controlled study. Drugs R D (2007) 8, 383–91.

3. Lala LG, D’Mello PM, Naik SR. Pharmacokinetic and pharmacodynamic studies on interaction of “Trikatu” with diclofenac sodium. J Ethnopharmacol (2004) 91, 277–80.

4. Karan RS, Bhargava VK, Garg SK. Effect of Trikatu on the pharmacokinetic profile of indomethacin in rabbits. Indian J Pharmacol (1999) 31, 160–161.

5. Mujumdar AM, Dhukey JN, Deshmukh VK, Naik SR. Effect of piperine on bioavailability of oxyphenylbutazone in rats. Indian Drugs (1999) 36, 123–6.

6. Hiwale AR, Dhuley JN, Naik SR. Effect of co-administration of piperine on pharmacokinetics of beta-lactam antibiotics in rats. Indian J Exp Biol (2002) 40, 277–81

7. Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF. Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4. J Pharmacol Exp Ther (2002) 302, 645–50.

8. Han Y, Tan TMC, Lim L-Y. In vitro and in vivo evaluation of the effects of piperine on P-gp function and expression. Toxicol Appl Pharmacol (2008) 230, 283–9.

9. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PSSR. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med (1998) 64, 353–6

10. Badmaev V, Majeed M, Prakash L. Piperine derived from black pepper increases the plasma levels of coenzyme Q10 following oral supplementation. J Nutr Biochem (2000) 11, 109–13.

11. Velpandian T, Jasuja R, Bhardwaj RK, Jaiswal J, Gupta SK. Piperine in food: interference in the pharmacokinetics of phenytoin. Eur J Drug Metab Pharmacokinet (2001) 26, 241–8.

12. Bano G, Amla V, Raina RK, Zutschi U, Chopra CL. The effect of piperine on pharmacokinetics of phenytoin in healthy volunteers. Planta Med (1987) 53, 568–9.

13. Pattanaik S, Hota D, Prabhakar S, Kharbanda P, Pandhi P. Effect of piperine on the steady-state pharmacokinetics of phenytoin in patients with epilepsy. Phytother Res (2006) 20, 683–6.

14. Bano G, Raina RK, Zutshi U, Bedi KL, Johri RK, Sharma SC. Effect of piperine on bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers. Eur J Clin Pharmacol (1991) 41, 615–17.