INVESTIGATION OF CYP1A INTERACTION POTENTIAL OF WITHANIA SOMNIFERA IN RAT AND HUMAN LIVER MICROSOMES

  • Jay Savai PhD Research Scholar
  • Nancy Pandita SVKM’s NMIMS, Vile Parle
  • Meena Chintamaneni Shobhaben Pratapbhai Patel

Abstract

Objective: The aim of this study was to investigate CYP1A interaction of crude extracts (ethanolic, methanolic, hydromethanolic & aqueous) of Withania somnifera and its principal phytoconstituents (withaferin-A and withanolide-A) in rat and human liver microsomes.

Methods: In vitro study were carried out in both rat & human liver microsomes while, in vivo CYP1A interaction potential was investigated by administering the methanolic extract of Withania somnifera orally at a dose of 500 mg/kg in male Wistar rats using probe substrate technique.

Results: The results of this study revealed that IC50 values of all the crude extracts of Withania somnifera and its principal phytoconstituents (withaferin–A & withanolide–A) were found to be >640 µg/ml and >32 µM respectively, for CYP1A enzyme both in rats and humans. However, in vivo pharmacokinetic study of co-administered methanolic extract of Withania somnifera and phenacetin, revealed that the crude extract lead to an approximate 1.5 fold (31%) decrease in AUC 0-24h (p < 0.05). Elimination rate constant (Ke) increased by 2 fold (48%) and half-life (T1/2) decreased by 1.8 fold (43%).

Conclusion: The results of this study suggested that Withania somnifera showed no in vitro CYP1A inhibition in both rats and humans. However, in vivo administration of methanolic extract of Withania somnifera significantly induced CYP1A enzyme & subsequently altered the pharmacokinetics profile of phenacetin in rats; indicating a potential for herb-drug interactions.

 

Keywords: Withania somnifera, CYP1A interaction, Phenacetin, Human liver microsomes, Pharmacokinetics, Herb-drug interaction

Downloads

Download data is not yet available.

Author Biography

Jay Savai, PhD Research Scholar
Department of Phamracology

References

1. Ponnusankar S, Pandit S, Babu R, Bandyopadhyay A, Mukherjee PK. Cytochrome P450 inhibitory potential of Triphala—A rasayana from ayurveda. J Ethnopharmacol 2011;133:120–5.
2. Obach SR. Inhibition of human cytochrome P450 enzymes by constituents of st. john’s wort, an herbal preparation used in the treatment of depression. J Pharmacol Exp Ther 2010;294:88-95.
3. Liwei Hu, Wen Xu, Xi Zhang, Juan Su, Xinru Liu, Haiyun Li, et al. In vitro and in vivo evaluations of Cytochrome P450 1A2 interactions with nuciferine. J Pharm Pharmacol 2010;62:658–62.
4. Pius SF, Bouic PJ, Rosenkranz B. An overview of the evidence and mechanisms of herb–drug interactions. Front Pharmacol 2012;3:1–19.
5. Guengerich PF. Cytochrome P450 Enzymes. Am Sci 1993;81(5):440-7.
6. Mishra LC, Singh BB, Dagenais S. Scientific basis for the therapeutic use of Withania somnifera (ashwagandha): a review. Altern Med Rev 2000;5:334-46.
7. Bhatnagar M, Sisodia SS, Bhatnagar R. Antiulcer and antioxidant activity of Asparagus racemosa WILLD and Withania somnifera DUNAL in rats. Ann NY Acad Sci 2005;1056:261-78.
8. Bhattacharya A, Ghosal S, Bhattacharya SK. Anti-oxidant effect of Withania somnifera glycowithanolides in chronic foot shock stress induced perturbations of oxidative free radical scavenging enzymes and lipid peroxidation in rat frontal cortex and striatum. J Ethnopharmacol 2001;74:1-6.
9. Gupta SK, Dua A, Vohra BP. Withania somnifera (ashwagandha) attenuates antioxidant defense in aged spinal cord and inhibits copper induced lipid peroxidation and protein oxidative modifications. Drug Metabol Drug Interact 2003;19:211-22.
10. Scartezzini P, Speroni E. Review on some plants of Indian traditional medicine with antioxidant activity. J Ethnopharmacol 2007;71:23-43.
11. Cooley K, Szczurko O, Perri D, Mills EJ, Bernhardt B, Zhou Q, et al. Naturopathic care for anxiety: a randomized controlled trial ISRCTN78958974. PLoS One 2009;4:6628.
12. Ahmad MK, Mahdi AA, Shukla KK, Islam N, Rajender S, Madhukar D, et al. Withania somnifera improves semen quality by regulating reproductive hormone levels and oxidative stress in seminal plasma of infertile males. Fertil Steril 2010;94:989-96.
13. Murthy V, Ranjekar MR, Ramassamy PK, Deshpande C. Scientific basis for the use of Indian ayurvedic medicinal plants in the treatment of neurodegenerative disorders: ashwagandha. Cent Nerv Syst Agents Med Chem 2010;10:238-46.
14. Chaurasia ND, Uniyal GC, Lal P. Analysis of withanolides in root and leaf of withania somnifera by HPLC with photodiode array and evaporative light scattering detection. Phytochem Anal 2008;19:148–54.
15. Pradnya S, Walawalkar PS Serai, Iyer KR. Isolation and catalytic competence of different animal liver microsomal fractions prepared by calcium – aggregation method. Indian J Pharm Sci 2006;68(2):262-5.
16. Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J Biol Chem 1951;193:265-75.
17. Wrighton S, Ring B, Vandenbranden M. The use of in vitro metabolism techniques in the planning and interpretation of drug safety studies. Toxicol Pathol 1995;23(2):199-208.
18. Varghese A, Savai J, Pandita N, Gaud R. Species related differences in in vitro metabolism of phenacetin, a probe substrate for CYP1A enzyme, and enzyme kinetic parameters of phenacetin. Int J Pharm Med Bio Sci 2014;3(2):21-30.
19. Guidance for Industry. Drug Interactions Studies: study design, data analysis and implications for dosing and labeling; 2006. /http://www.fda.gov/cder, http://www.fda.gov./cder/guidance/6695dft.pdfS.Accessed 26 October 2014.
20. Girdhari LG, Rana AC. Plant review withania somnifera (Ashwagandha): a review. Pharmacogn Rev 2007;1(1):129-36.
21. Yan P. In vitro modulatory effects of Andrographis paniculata, Centella asiatica and Orthosiphon stamineus on cytochrome P450 2C19 (CYP2C19). J Ethnopharmacol 2011;133:881-7.
22. Miroslaw M, Katarzyna ZS, Marta J, Monika M. In vivo effect of diallyl sulfide and cimetidine on phenacetin metabolism and bioavailability in rat. Acta Bio Polonica 2002;49(1):249-56.
23. Weiner MA, Weiner J. Ashwagandha (India ginseng). In: Herbs that Heal. Quantum Books, Mill Valley (CA); 1994.
24. Elsakka M, Grigorescu E, Stanescu U, Stanescu U, Dorneanu V. New data referring to chemistry of Withania somnifera species. Rev Med Chir Soc Med Nat Iasi 1990;94(2):385-7.
25. Ganzera M, Choudhary MI, Khan IA. Quantitative HPLC analysis of withanolides in Withania somnifera. Fitoterapia 2003;74(1-2):68-76.
26. Kelly JP. Recent trends in use of herbal and other natural products. Arch Intern Med 2005;165:281–6.
27. Badala S. Cytochrome P450 1 enzyme inhibition and anticancer potential of chromene amides from amyris plumier. Fitoterapia 2011;82:230–6.
28. Gonzalez FJ, Yu AM. Cytochrome P450 and xenobiotic receptor humanized mice. Ann Rev Pharmacol Toxicol 2006;46:41–64.
29. Savai J, Varghese A, Pandita N. Lack of the cytochrome P450 3A interaction of methanolic extract of Withania somnifera, Withaferin A, Withanolide A and Withanoside IV. J Pharm Negat Results 2013;4(1):26-32.
30. Levy G, Koysooko R. Pharmacokinetic analysis of the effect of theophylline on pulmonary function in asthmatic children. J Pediatr 1975;86:789–93.
Statistics
352 Views | 1218 Downloads
How to Cite
Savai, J., N. Pandita, and M. Chintamaneni. “INVESTIGATION OF CYP1A INTERACTION POTENTIAL OF WITHANIA SOMNIFERA IN RAT AND HUMAN LIVER MICROSOMES”. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 7, no. 2, Dec. 2014, pp. 273-8, https://innovareacademics.in/journals/index.php/ijpps/article/view/4060.
Section
Original Article(s)