Download PDF
CC BY-NC-ND 4.0 · Planta Medica International Open 2021; 8(01): e10-e18
DOI: 10.1055/a-1375-6570
Original Article

Carbamazepine Shows Plasma and Tissue Pharmacokinetic Interactions with Ajuga bracteosa Extract in Rats

Ejaz Ahmad
1   Department of Chemistry, Government College University Lahore, Pakistan
,
Muhammad Jahangir 
1   Department of Chemistry, Government College University Lahore, Pakistan
,
Saiqa Ishtiaq
2   Punjab University College of Pharmacy, University of Punjab, Lahore, Pakistan
,
Hafiz Muhammad Faizan Haider
1   Department of Chemistry, Government College University Lahore, Pakistan
,
Pervaiz Akhtar Shah
2   Punjab University College of Pharmacy, University of Punjab, Lahore, Pakistan
,
Nadeem Irfan Bukhari
2   Punjab University College of Pharmacy, University of Punjab, Lahore, Pakistan
› Author Affiliations
› Further Information
   Permissions and Reprints

Abstract

Carbamazepine (CBZ) is the first-line anticonvulsant drug with a narrow therapeutic index (NTI) and is a substrate for CYP3A4 and MRP-2. Ajuga bracteosa (AB), family Lamiaceae is widely used to treat epilepsy, gastric diseases, and protects against liver damage in folk. It contains bioactive metabolites, which are powerful inhibitors of CYP3A4, CYP3A5, CYP19, CYP2C19 enzymes and P-gp transporter. Concomitant use of NTI drugs with herbs, like AB increase the chances of herb-drug interactions (HDIs). This study was aimed to analyze the Ajuga bracteosa crude extract (ABCE) and to investigate its effect on the pharmacokinetics of CBZ in rats. In the pre-treatment study, rats received ABCE (1000 mg/kg) orally for 14 days, followed by a single dose of CBZ (80 mg/kg) on the 15th day. In the co-administration study, single doses of ABCE and CBZ were administered concomitantly in one session. All the doses were administered in 0.5% carboxymethylcellulose (CMC) as a vehicle. HPLC analysis showed that extract contained 1.3 mg/g ursolic acid, 2.1 mg/g sitosterol and 2.9 mg/g stigmasterol. Non-compartmental pharmacokinetic analysis showed an increase in Cmax, AUC0-∞, MRT, and t1/2 with a decrease in tmax, Vd and Cl of CBZ in both, pre-treated and co-administered groups vs controls. An increase in CBZ concentration in liver tissue of both pre-treated as well as co-administered animals was observed as compared to control. The above results suggested possible HDIs between AB and CBZ thus, may warrant CBZ dose adjustment in epileptic patients with simultaneous administration of AB or its products.

Key words

Ajuga bracteosa (family Lamiaceae) - bioavailability - carbamazepine - herb-drug pharmacokinetic interactions - HPLC analysis


Publication History

Received: 17 August 2020
Received: 03 November 2020

Accepted: 25 January 2021

Article published online:
12 March 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Beghi E, Giussani G, Nichols E, Abd-Allah F, Abdela J, Abdelalim A, Abraha HN, Adib MG, Agrawal S, Alahdab F. Global, regional, and national burden of epilepsy, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18: 357-375
    CrossrefPubMedGoogle Scholar
  • 2 Khatri I, Iannaccone S, Ilyas M, Abdullah M, Saleem SJ. Epidemiology of epilepsy in Pakistan: review of literature. J Pak Med Assoc 2003; 53: 594-596
    PubMedGoogle Scholar
  • 3 Buenafe OE, Orellana-Paucar A, Maes J, Huang H, Ying X, De Borggraeve W, Crawford AD, Luyten W, Esguerra CV, de Witte P. Tanshinone IIA exhibits anticonvulsant activity in zebrafish and mouse seizure models. ACS Chem Neurosci 2013; 4: 1479-14874
    CrossrefPubMedGoogle Scholar
  • 4 Shetty AK, Upadhya DJN, Reviews B. GABA-ergic cell therapy for epilepsy: Advances, limitations and challenges. Neurosci Biobehav Rev 2016; 62: 35-47
    CrossrefPubMedGoogle Scholar
  • 5 Marais A, Steenkamp V, Du Plooy WJ. Conditions frequently self-treated with herbal remedies by patients visiting a tertiary hospital in Gauteng, South Africa. S Afr Fam Pract 2015; 57: 8-11
    CrossrefPubMedGoogle Scholar
  • 6 Devi PU, Manocha A, Vohora D. Seizures, antiepileptics, antioxidants and oxidative stress: An insight for researchers. Expert Opin Pharmacother 2008; 9: 3169-3177
    CrossrefPubMedGoogle Scholar
  • 7 Alrashood S. Carbamazepine. In Profiles of Drug Substances, Excipients and Related Methodology. Elsevier; 2016: 133-321
    Google Scholar
  • 8 Xu W, Chen Y-L, Zhao Y, Wang L-J, Li J-J, Liu C-F. A clinical study of toxication caused by carbamazepine abuse in adolescents. BioMed Res Int 2018; 2018
    PubMedGoogle Scholar
  • 9 Giessmann T, May K, Modess C, Wegner D, Hecker U, Zschiesche M, Dazert P, Grube M, Schroeder E, Warzok R. Carbamazepine regulates intestinal P-glycoprotein and multidrug resistance protein MRP2 and influences disposition of Talinolol in humans. Clinical Pharmacology Ther Clin Risk Manag 2004; 76: 192-200
    CrossrefPubMedGoogle Scholar
  • 10 Brady JM, Cherrington NJ, Hartley DP, Buist SC, Li N, Klaassen CD. Tissue distribution and chemical induction of multiple drug resistance genes in rats. Drug Metab Dispos 2002; 30: 838-844
    CrossrefPubMedGoogle Scholar
  • 11 Sabariah NH, Siti MS, Nor AC, Khan AH. Cholestatic hepatitis secondary to carbamazepine treatment with ursodeoxycholic acid-A case report. Trop J Pharm Res 2014; 13: 1745-1747
    PubMedGoogle Scholar
  • 12 Akhtar N, Rashid A, Murad W, Bergmeier EJ. Diversity and use of ethno-medicinal plants in the region of Swat, North Pakistan. J Ethnobiol Ethnomedicine 2013; 9: 25
    CrossrefPubMedGoogle Scholar
  • 13 Qasim S, Uttra AM, Hasan UH, Batool A. Evaluation of anticonvulsant potential of aqueous meth-anolic extract and various fractions of Ajuga bracteosa wall. Journal of Experimental Applied Animal Sciences 2017; 2: 137-146
    CrossrefPubMedGoogle Scholar
  • 14 Upadhyay S, Patel V, Patel A, Upadhyay U, Patel N. Ajuga bracteosa: A promising herb. Pharma Sci Monit 2012; 3: 3
    PubMedGoogle Scholar
  • 15 Kayani WK, Dilshad E, Ahmed T, Ismail H, Mirza B. Evaluation of Ajuga bracteosa for antioxidant, anti-inflammatory, analgesic, antidepressant and anticoagulant activities. BMC Complement Altern Med 2016; 16: 375
    CrossrefPubMedGoogle Scholar
  • 16 Darbour N, Bayet C, Doreau A, Raad I, Phung BH, Dumontet C, Di Pietro A, Dijoux-Franca M-G, Guilet D. Selective modulation of P-glycoprotein activity by steroidal saponines from Paris polyphylla. Fitoterapia 2009; 80: 39-42
    CrossrefPubMedGoogle Scholar
  • 17 Najar I, Sachin B, Sharma S, Satti N, Suri K, Johri R. Modulation of P-glycoprotein ATPase activity by some phytoconstituents. Phytotherapy Research: An International Journal Devoted to Pharmacological Toxicological Evaluation of Natural Product Derivatives 2010; 24: 454-458
    CrossrefPubMedGoogle Scholar
  • 18 Peter A, SMET P. Herbal remedies. N Engl J Med 2002; 347: 2046-2056
    CrossrefPubMedGoogle Scholar
  • 19 Zhou S-F, Zhou Z-W, Li C-G, Chen X, Yu X, Xue CC, Herington A. Identification of drugs that interact with herbs in drug development. Drug Discov Today 2007; 12: 664-673
    CrossrefPubMedGoogle Scholar
  • 20 Klepser TB, Doucette WR, Horton MR, Buys LM, Ernst ME, Ford JK, Hoehns JD, Kautzman HA, Logemann CD, Swegle JM. Assessment of patients’ perceptions and beliefs regarding herbal therapies. Pharmacotherapy: The Journal of Human Pharmacology Drug Therapy 2000; 20: 83-87
    CrossrefPubMedGoogle Scholar
  • 21 Kennedy J. Herb and supplement use in the US adult population 2005; 27: 1847-1858
    PubMed
  • 22 Landmark CJ, Patsalos PN. Interactions between antiepileptic drugs and herbal medicines. B Latinoam Caribe Pl 2008; 7: 109-118
    PubMedGoogle Scholar
  • 23 Chi Y-C, Lin S-P, Hou Y-C. A new herb–drug interaction of Polygonum cuspidatum, a resveratrol-rich nutraceutical, with carbamazepine in rats. Toxicol Appl Pharmacol 2012; 263: 315-322
    CrossrefPubMedGoogle Scholar
  • 24 Bader Badi Alsulays SJ, Raish M, Ansari MA, Ahmad A, Alalaiwe A, Alshahrani SM, Alshetaili AS, Ansari MJ, Alshehri SM. Influences of ferulic acid on pharmacokinetics of carbamazepine in rats: possible mechanism of herb/food-drug Interactions. Pharmacology 2019; 15: 978-985
    PubMedGoogle Scholar
  • 25 Shi L, Dang X-L, Liu X-Y, Wei H-M, Yang M-M, Zhang Y. Effect of sophora flavescens on the pharmacokinetics of carbamazepine in rats. Archives of Pharmacal Research 2014; 37: 1617-1623
    CrossrefPubMedGoogle Scholar
  • 26 Emad R, Mallah E, Shahin F, El-Hajji FD, Dayyih WA, Idkaidek N, Abu-Qatouseh L, Jaradat D, Arafat T. Determination of carbamazepine in rat plasma by using high performance liquid chromatography (HPLC) in presence of some traditional beverages (tamarind, mango, sugarcane, red bull) and its pharmacokinetic applications. Int J Biol Pharm Allied Sci 2018; 7: 1908-1921
    PubMedGoogle Scholar
  • 27 König J, Nies AT, Cui Y, Keppler D. MRP2, the Apical Export Pump for Anionic Conjugates. Academic Press; London: 2003
    CrossrefGoogle Scholar
  • 28 Dietrich C, Geier A, Elferink RO. ABC of oral bioavailability: transporters as gatekeepers in the gut. Gut 2003; 52: 1788-1795
    CrossrefPubMedGoogle Scholar
  • 29 Löscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci 2005; 6: 591-602
    CrossrefPubMedGoogle Scholar
  • 30 Schaub TP, Kartenbeck J, Konig J, Spring H, Dorsam J, Staehler G, Storkel S, Thon WF, Keppler D. Expression of the MRP2 gene-encoded conjugate export pump in human kidney proximal tubules and in renal cell carcinoma. J Am Soc Nephrol 1999; 10: 1159-1169
    CrossrefPubMedGoogle Scholar
  • 31 Potschka H, Fedrowitz M, Löscher W. P-glycoprotein and multidrug resistance-associated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain. Neuroreport 2001; 12: 3557-3560
    CrossrefPubMedGoogle Scholar
  • 32 Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N Engl J Med 2011; 365: 919-926
    CrossrefPubMedGoogle Scholar
  • 33 Venkataramanan R, Komoroski B, Strom S. In vitro and in vivo assessment of herb drug interactions. Life Sci 2006; 78: 2105-2115
    CrossrefPubMedGoogle Scholar
  • 34 Kim K-A, Lee J-S, Park H-J, Kim J-W, Kim C-J, Shim I-S, Kim N-J, Han S-M, Lim S. Inhibition of cytochrome P450 activities by oleanolic acid and ursolic acid in human liver microsomes. Life Sci 2004; 74: 2769-2779
    CrossrefPubMedGoogle Scholar
  • 35 Hussain J, Begum N, Hussain H, Khan FU, Rehman NU, Al-Harrasi A, Ali L. Ajuganane: a new phenolic compound from Ajuga bracteosa. Nat Prod Commun 2012; 7: 1934578X1200700518
    PubMedGoogle Scholar
  • 36 Nair VD, Foster BC, Arnason JT, Mills EJ, Kanfer I. In vitro evaluation of human cytochrome P450 and P-glycoprotein-mediated metabolism of some phytochemicals in extracts and formulations of African potato. Phytomedicine 2007; 14: 498-507
    CrossrefPubMedGoogle Scholar
  • 37 El-Readi MZ, Hamdan D, Farrag N, El-Shazly A, Wink M. Inhibition of P-glycoprotein activity by limonin and other secondary metabolites from Citrus species in human colon and leukaemia cell lines. Eur J Pharmacol 2010; 626: 139-145
    CrossrefPubMedGoogle Scholar
  • 38 Vijayakumar TM, Kumar RM, Agrawal A, Dubey GP, Ilango K. Comparative inhibitory potential of selected dietary bioactive polyphenols, phytosterols on CYP3A4 and CYP2D6 with fluorometric high-throughput screening. J Food Sci Technol 2015; 52: 4537-4543
    CrossrefPubMedGoogle Scholar
  • 39 Kerr BM, Thummel KE, Wurden CJ, Klein SM, Kroetz DL, Gonzalez FJ, Levy R. Human liver carbamazepine metabolism: Role of CYP3A4 and CYP2C8 in 10, 11-epoxide formation. Biochem Pharmacol 1994; 47: 1969-1979
    CrossrefPubMedGoogle Scholar
  • 40 Potschka H, Fedrowitz M, Löscher W. Multidrug resistance protein MRP2 contributes to blood-brain barrier function and restricts antiepileptic drug activity. J Pharmacol Exp Ther 2003; 306: 124-131
    CrossrefPubMedGoogle Scholar
  • 41 Rodrigues M, Alves G, Francisco J, Fortuna A, Falcão A. Herb-drug pharmacokinetic interaction between carica papaya extract and amiodarone in rats. JPharmPharma 2014; 17: 302-315
    PubMedGoogle Scholar
  • 42 Jansson R, Bredberg U, Ashton M. Prediction of drug tissue to plasma concentration ratios using a measured volume of distribution in combination with lipophilicity. J Pharm Sci 2008; 97: 2324-2339
    CrossrefPubMedGoogle Scholar
  • 43 Annegers J. Total body water in rats and in mice. Proceedings of the Society for Experimental Biology Medicine & Global Survival 1954; 87: 454-456
    CrossrefPubMedGoogle Scholar
  • 44 Charifson PS, Walters WP. Acidic and basic drugs in medicinal chemistry: A perspective. J Med Chem 2014; 57: 9701-9717
    CrossrefPubMedGoogle Scholar
  • 45 Dawes M, Chowienczyk PJ. Pharmacokinetics in pregnancy. Best practice research Clinical obstetrics gynaecology 2001; 15: 819-826
    CrossrefPubMedGoogle Scholar
  • 46 Gudin J. Opioid therapies and cytochrome p450 interactions. Journal of pain symptom management 2012; 44: S4-S14
    CrossrefPubMedGoogle Scholar
  • 47 Ladda MA, Goralski KB. The effects of CKD on cytochrome P450–mediated drug metabolism. Adv Chronic Kidney Dis 2016; 23: 67-75
    CrossrefPubMedGoogle Scholar
  • 48 Abuhelwa AY, Williams DB, Upton RN, Foster DJ. Food, gastrointestinal pH, and models of oral drug absorption. Eur J Pharm Biopharm 2017; 112: 234-248
    CrossrefPubMedGoogle Scholar
  • 49 Panakanti R, Narang AS. Impact of excipient interactions on drug bioavailability from solid dosage forms. In Excipient Applications in Formulation Design and Drug Delivery. Springer; 2015: 273-310
    Google Scholar
  • 50 Gerber W, Steyn JD, Kotzé AF, Hamman JH. Beneficial pharmacokinetic drug interactions: A tool to improve the bioavailability of poorly permeable drugs. Pharmaceutics 2018; 10: 106
    CrossrefPubMedGoogle Scholar
  • 51 Bialer M, Rene’H L, Perucca E. Does carbamazepine have a narrow therapeutic plasma concentration range?. Ther Drug Monit 1998; 20: 56-59
    CrossrefPubMedGoogle Scholar
  • 52 Foye WO. Foye’s Principles of Medicinal Chemistry. Lippincott Williams & Wilkins; 2008
    Google Scholar
  • 53 Kaiboriboon K, Guevara M, Alldredge BK. Understanding herb and dietary supplement use in patients with epilepsy. Epilepsia 2009; 50: 1927-1932
    CrossrefPubMedGoogle Scholar
  • 54 Xu X-H, Su Q, Zang Z-H. Simultaneous determination of oleanolic acid and ursolic acid by RP-HPLC in the leaves of Eriobotrya japonica Lindl. JPharm Anal 2012; 2: 238-240
    CrossrefPubMedGoogle Scholar
  • 55 Mukhtar HM, Singh A, Soni V, Singh A, Kaur H. Development and validation of RP-HPLC method for the determination of stigmasterol in the botanical extract of Ficus deltoidea. Nat Prod Res 2019; 33: 2868-2872
    CrossrefPubMedGoogle Scholar
  • 56 Shah UM, Patel S, Patel P, Hingorani L, Jadhav R. Development and validation of a simple isocratic HPLC method for simultaneous estimation of phytosterols in Cissus quadrangularis. Indian J Pharm Sci 2010; 72: 753
    CrossrefPubMedGoogle Scholar