Bioenhancer Explained

Bioenhancers or biopotentiators[1] or bioavailability enhancers is a new chapter in medical science first scientifically established in 1979 after the discovery of world's first bioenhancer piperine.[2] It is a pocket friendly drug technology which reduces the destruction, wastage and elimination of several orally administered drugs inside the body.

Definition Bioenhancers are defined as substances that increase the bioavailability leading to increased bioefficacy of active substances with which they are combined without having any pharmacological activity of their own at the dose used.[3] They may enhance bioavailability of allopathic drugs, vitamins, nutrients and toxins depending on its mechanism of action. For example, piperine increases bioavailability of several nutrients such as beta-carotene,[4] vitamin A, vitamin B6, coenzyme Q10,[5] [6] drugs such as phenytoin,[7] theophylline,[8] propanolol[9] and a toxin called aflatoxin B1.[10]

Increased Bioavailabiity means increased levels of drug in the blood stream available for drug action. Increased Bioefficacy means the increased effectiveness of the drug due to increased bioavailability or due to other mechanisms.

History

An observation made in 1929 by Bose describes an increased antiasthmatic activity of vasaka leaves when pepper was added to it. No explanation for this observation was given nor any studies were done to explain the observation. The breakthrough in bioenhancers was finally provided about 50 years later in 1979 by Dr. C. K. Atal, director of RRL Jammu, who was researching on medicinal plants. [11] Bioenhancers or bioavailability enhancers as a term and chapter did not exist in any modern scientific literature prior to 1979. The term bioavailability enhancers was first coined in 1979 at Indian Institute of Integrative medicine, Jammu, formerly RRL, Jammu, by Indian scientists Dr. C. K. Atal, the Director of institute RRL Jammu proposed the hypothesis of increased bioavailability of drugs from a clue during research on traditional medicinal drugs. Subsequently, the concept of bioavailability enhancers was scientifically researched and scientifically established by him and his research team at RRL Jammu. The institute then discovered and scientifically validated Piperine as the world's first bioenhancer using Sparteine and Vasicine which became the world's first experimentally bioenhanced drugs. Dr. Atal also initiated the bioenhanced anti tubercular drug research project using Rifampicin[12] which later resulted in development of world's first bioenhanced anti tubercular drug formulation. This DCGI approved formulation was officially released by Indian government at Anusandhan Bhawan Delhi on world tuberculosis day 2011, and also presented to Mr. Bill Gates, chairman of Microsoft same day at a function at Le Meridian in Delhi.

After the discovery of bioenhancer Piperine in 1979, a new chapter was added in medical science. Since then it has generated global interest and research in the field and has led to discovery of many other new bioenhancers. Piperine remains the most potent and extensively researched bioenhancer till date. It is safe, effective, extremely economical and easily manufactured for commercial use. It is also a broad spectrum bioenhancer acting on several classes of modern drugs as noted elsewhere.[13] [14] [15]

Classification

Bioenhancers can be classified according to their source of origin, either plant based or animal based or else according to their site of action. Bioenhancers so far almost exclusively discovered in plants, increase the bioavailability of other substances in different ways:

Advantages of Bioenhancers

Reduced dose

Bioenhancers prevent this wastage of ingested drugs inside the body and increase quantity of drug reaching the blood, therefore a reduced dosage of oral drug is sufficient to achieve the desired blood levels.

Reduced raw material consumption

This reduced dose needed for desired drug action means beneficial effect on raw materials consumption required to develop drugs which is a great savings for any country.

Ecological advantage

This also translates into ecological advantage in case of rare and expensive plant based drugs as less trees or plant have to be consumed to produce drugs, an example being the costly anti cancer drug taxol derived from very slow growing yew trees.

Reduced drug cost

This reduced dose in turn also reduces the cost of drugs. Billions of dollars are wasted globally in various countries due to poor bioavailability of drugs, which is a huge financial burden on any nation, particularly poor developing countries. This is particularly relevant in serious and dreaded diseases on mankind like tuberculosis for which treatment is expensive, toxic and prolonged and for which an emergency situation has been declared by UN due to emergence of AIDS and development of serious drug resistance.

Reduced adverse reactions

This reduced dose in turn also reduces the side effects of drugs.

Improved compliance

Lesser side effects also improve drug tolerability, drug compliance and promote completion of treatment.

Reduced drug resistance

This improved tolerability and compliance in turn reduces risk of developing dangerous drug resistance.

Added hepatoprotective and gastroprotective actions

Even though bioenhancers are not pharmacologically active,[16] they can have added benefits such as reduction of gastrointestinal side effects and hepatotoxicity of primary active drug which further makes formulation safer, better tolerated and again reduces drug toxicity and drug resistance.

For example, by reducing the required dose of expensive toxic Rifampicin by 60 percent, it correspondingly reduces the cost and side effects of Rifampicin while treating the dreaded disease Tuberculosis.[17] This is a great advantage to poor patients, poor countries and for dreaded diseases of man.

Examples of bioenhancers

The following examples of bioenhancers give an insight into the current pharmacological research and show how with pepper, curry, ginger and other herbal ingredients in food a lack of nutrients or insufficient effects of active agents can be prevented:

Piperine, an ingredient of pepper, promotes intestinal absorption by activation of the γ-glutamyltranspeptidase and inhibits the degradation of many compounds, by inhibiting different enzymes: aryl hydrocarbon hydroxylase (AHH),[18] ethylmorphine N-demethylase,[19] Uridine diphosphate glucuronic_acid,[20] Uridine diphosphate glucuronyltransferase (UGT),[21] P-glycoprotein,[22] [23] CYP2EI[24] and CYP3A4.[25] [26] Especially the latter two enzymes contribute significantly to the first-pass effect.

Piperine acts as bioenhancer to vitamins (A, B1, B2, B6, C, D, E, K), beta-carotene,[27] amino acids (lysine, isoleucine, leucine, threonine, valine, tryptophan, phenylalanine, and methionine), minerals (iodine, calcium, iron, zinc, copper, selenium, magnesium, potassium, manganese), herbal compounds (including ginsenosides, Pycnogenol, resveratrol, epigallocatechin, curcumin[28]), and drugs (such as ampicillin, carbamazepine,[29] chlorzoxazone,[30] diclofenac,[31] fexofenadine,[32] ibuprofen,[33] rifampicin,[34] tetracycline, pyrazinamide).

Allicin from garlic enhances the effect of the fungicide amphotericin B on yeast cells by affecting the transport of the fungicide into the yeast vacuole.

Curcumin which inter alia is found in curry inhibits like piperine the enzyme CYP3A4 and affects the transport function of P-glycoprotein. In combination with curcumin an increased bioavailability of the active compounds celiprolol and midazolam was detected.

Ginger promotes due to the gingerols the intestinal absorption of many compounds (including drugs) and elements. In most cases, ginger acts synergistically with piperine.

Glycyrrhizin, a saponin of the liquorice plant, promotes the action of numerous antibiotics and the antifungal agent clotrimazole.

Quercetin, a flavonoid from fruits and leaves, acts like curcumin and piperine. It increases the bioavailability of the active agent paclitaxel used to treat cancer.

Carum carvi, a herb from Apiaceae enhances the bioavailability of anti tuberculosis drugs such as rifampicin, isoniazid, and pyrazinamide.[35]

Application of research results

The bioenhancer technology is primarily targeted for toxic drugs, expensive drugs, scarce drugs, poorly bioavailable drugs or drugs which need to be given for prolonged periods. However it can also be used in any drugs influenced by bioenhancers. The discovery and characterization of bioenhancers has led to several patent applications. Piperine is marketed as bioenhancer in mono preparations and as a component of dietary supplements that contain different vitamins, curcumin, resveratrol or Coenzyme Q10.

Since bioenhancers can reduce the dosage and cost of expensive medication while making treatment safer, its application has for the first time been done in humans in treating tuberculosis for which the existing drugs are toxic and expensive and need to be administered over prolonged periods. In India where low treatment costs for medical care are essential, the drug Risorine is approved against tuberculosis. Besides the antibiotics rifampicin and isoniazid it contains piperine.[36]

References

Notes and References

  1. Randhawa GK, Kullar JS, Rajkumar . Bioenhancers from mother nature and their applicability in modern medicine . . 1 . 1 . 5–10 . January 2011 . 23776764 . 3657948 . 10.4103/2229-516X.81972 . free .
  2. Atal CK. A breakthrough in drug bioavailability-a clue from age old wisdom of Ayurveda.. 1979 . IDMA Bulletin. 483–484.
  3. Randhawa GK, Kullar JS, Rajkumar . Bioenhancers from mother nature and their applicability in modern medicine . . 1 . 1 . 5–10 . January 2011 . 23776764 . 3657948 . 10.4103/2229-516X.81972 . free .
  4. Badmaev. Vladimir. Majeed. Muhammed. Norkus. Edward P.. Piperine, an alkaloid derived from black pepper increases serum response of beta-carotene during 14-days of oral beta-carotene supplementation. Nutrition Research. 19. 3. 1999. 381–388. 0271-5317. 10.1016/S0271-5317(99)00007-X.
  5. Atal N, Bedi KL . Bioenhancers: Revolutionary concept to market . . 1 . 2 . 96–9 . April 2010 . 21836795 . 3151395 . 10.4103/0975-9476.65073 . free .
  6. Badmaev V, Majeed M, Prakash L . Piperine derived from black pepper increases the plasma levels of coenzyme Q10 following oral supplementation . . 11 . 2 . 109–13 . February 2000 . 10715596 . 10.1016/s0955-2863(99)00074-1 .
  7. Bano G, Amla V, Raina RK, Zutshi U, Chopra CL . The effect of piperine on pharmacokinetics of phenytoin in healthy volunteers . . 53 . 6 . 568–9 . December 1987 . 3444866 . 10.1055/s-2006-962814 . 260249825 .
  8. 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 . . 41 . 6 . 615–7 . 1991 . 1815977 . 10.1007/BF00314996 . 28817165 .
  9. 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 . . 41 . 6 . 615–7 . 1991 . 1815977 . 10.1007/BF00314996 . 28817165 .
  10. Allameh A, Saxena M, Biswas G, Raj HG, Singh J, Srivastava N . Piperine, a plant alkaloid of the piper species, enhances the bioavailability of aflatoxin B1 in rat tissues . . 61 . 3 . 195–9 . January 1992 . 1739943 . 10.1016/0304-3835(92)90287-6 .
  11. Randhawa GK, Kullar JS, Rajkumar . Bioenhancers from mother nature and their applicability in modern medicine . . 1 . 1 . 5–10 . January 2011 . 23776764 . 3657948 . 10.4103/2229-516X.81972 . free .
  12. 4044481 . 33 . 3 . Influence of piperine on rifampicin blood levels in patients of pulmonary tuberculosis . 1985 . J Assoc Physicians India . 223–4 . Zutshi . RK . Singh . R . Zutshi . U . Johri . RK . Atal . CK.
  13. Web site: World's first bioenhancer Piperine. http://www.iiim.res.in/award-ckatal.pdf. https://web.archive.org/web/20140826121232/http://www.iiim.res.in/award-ckatal.pdf. dead. 2014-08-26.
  14. Web site: RRL jammu drug research. 2014-08-23. https://web.archive.org/web/20141022014926/http://www.herbalnet.org/events.htm. 2014-10-22. dead.
  15. Bioenhancers of herbal origin. 3634921 . 23620848 . 10.1016/S2221-1691(13)60060-X. 3. 4 . 2013. Asian Pac J Trop Biomed. 253–66 . Kesarwani . K . Gupta . R . Mukerjee . A.
  16. Randhawa GK, Kullar JS, Rajkumar . Bioenhancers from mother nature and their applicability in modern medicine . . 1 . 1 . 5–10 . January 2011 . 23776764 . 3657948 . 10.4103/2229-516X.81972 . free .
  17. Web site: Bioenhancers.
  18. Atal CK, Dubey RK, Singh J . Biochemical basis of enhanced drug bioavailability by piperine: evidence that piperine is a potent inhibitor of drug metabolism . . 232 . 1 . 258–62 . January 1985 . 3917507 .
  19. Atal CK, Dubey RK, Singh J . Biochemical basis of enhanced drug bioavailability by piperine: evidence that piperine is a potent inhibitor of drug metabolism . . 232 . 1 . 258–62 . January 1985 . 3917507 .
  20. Singh J, Dubey RK, Atal CK . Piperine-mediated inhibition of glucuronidation activity in isolated epithelial cells of the guinea-pig small intestine: evidence that piperine lowers the endogeneous UDP-glucuronic acid content . . 236 . 2 . 488–93 . February 1986 . 3080587 .
  21. Atal CK, Dubey RK, Singh J . Biochemical basis of enhanced drug bioavailability by piperine: evidence that piperine is a potent inhibitor of drug metabolism . . 232 . 1 . 258–62 . January 1985 . 3917507 .
  22. 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 . . 302 . 2 . 645–50 . August 2002 . 12130727 . 10.1124/jpet.102.034728 . 7398172 .
  23. Bedada SK, Boga PK . The influence of piperine on the pharmacokinetics of fexofenadine, a P-glycoprotein substrate, in healthy volunteers . . 73 . 3 . 343–349 . March 2017 . 27981349 . 10.1007/s00228-016-2173-3 . 23346527 .
  24. Bedada SK, Boga PK . Effect of piperine on CYP2E1 enzyme activity of chlorzoxazone in healthy volunteers . . 47 . 12 . 1035–1041 . December 2017 . 27670974 . 10.1080/00498254.2016.1241450 . 44781331 .
  25. 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 . . 302 . 2 . 645–50 . August 2002 . 12130727 . 10.1124/jpet.102.034728 . 7398172 .
  26. Bedada SK, Appani R, Boga PK . Effect of Piperine on the Metabolism and Pharmacokinetics of Carbamazepine in Healthy Volunteers . . 67 . 1 . 46–51 . January 2017 . 27776366 . 10.1055/s-0042-118173 . 19626636 .
  27. Badmaev. Vladimir. Majeed. Muhammed. Norkus. Edward P.. Piperine, an alkaloid derived from black pepper increases serum response of beta-carotene during 14-days of oral beta-carotene supplementation. Nutrition Research. 19. 3. 1999. 381–388. 0271-5317. 10.1016/S0271-5317(99)00007-X.
  28. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS . Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers . . 64 . 4 . 353–6 . May 1998 . 9619120 . 10.1055/s-2006-957450 . 260252570 .
  29. Bedada SK, Appani R, Boga PK . Effect of Piperine on the Metabolism and Pharmacokinetics of Carbamazepine in Healthy Volunteers . . 67 . 1 . 46–51 . January 2017 . 27776366 . 10.1055/s-0042-118173 . 19626636 .
  30. Bedada SK, Boga PK . Effect of piperine on CYP2E1 enzyme activity of chlorzoxazone in healthy volunteers . . 47 . 12 . 1035–1041 . December 2017 . 27670974 . 10.1080/00498254.2016.1241450 . 44781331 .
  31. Bedada SK, Boga PK, Kotakonda HK . Study on influence of piperine treatment on the pharmacokinetics of diclofenac in healthy volunteers . . 47 . 2 . 127–132 . February 2017 . 27052193 . 10.3109/00498254.2016.1163752 . 20380337 .
  32. Bedada SK, Boga PK . The influence of piperine on the pharmacokinetics of fexofenadine, a P-glycoprotein substrate, in healthy volunteers . . 73 . 3 . 343–349 . March 2017 . 27981349 . 10.1007/s00228-016-2173-3 . 23346527 .
  33. Venkatesh S, Durga KD, Padmavathi Y, Reddy BM, Mullangi R . Influence of piperine on ibuprofen induced antinociception and its pharmacokinetics . . 61 . 9 . 506–9 . 2011 . 22029226 . 10.1055/s-0031-1296235 . 26472628 .
  34. Nageswari. A.D.. Rajanandh. M.G.. Uday. M.K.R.A.. Nasreen. R.J.. Pujitha. R.R.. Prathiksha. G.. Effect of rifampin with bio-enhancer in the treatment of newly diagnosed sputum positive pulmonary tuberculosis patients: A double-center study. Journal of Clinical Tuberculosis and Other Mycobacterial Diseases. 12. 2018. 73–77. 2405-5794. 10.1016/j.jctube.2018.07.002. 31720402. 6830140.
  35. Choudhary N, Khajuria V, Gillani ZH, Tandon VR, Arora E . Effect of Carum carvi, a herbal bioenhancer on pharmacokinetics of antitubercular drugs: A study in healthy human volunteers . . 5 . 2 . 80–4 . April 2014 . 24741485 . 3980549 . 10.4103/2229-3485.128027 . free .
  36. Atal . N . Bedi . KL . 2010 . Bioenhancers: revolutionary concept to market . J Ayurveda Integr Med . 1. 2. 96–99 . 3151395 . 21836795 . 10.4103/0975-9476.65073 . free .

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