Influence of Rifampicin Pre-treatment on the In vivo Pharmacokinetics of Metoclopramide in Pakistani Healthy Volunteers Following Concurrent Oral Administration

Author(s): Iram Kaukab, Syed Nisar Hussain Shah, Muhammad Asad Abrar, Naveed Anwer, Ghulam Murtaza*

Journal Name: Current Drug Metabolism

Volume 21 , Issue 4 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Metoclopramide is metabolized by various cytochrome P450 (CYP) enzymes such as CYP3A4, CYP1A2, CYP2D6, CYP2C9, and CYP2C19. Rifampicin is a non-selective inducer of P-glycoprotein (P-gp) and CYP enzymes such as CYP3A4 and others.

Objective: This study was aimed at the evaluation of rifampicin’s enzyme induction effect on the pharmacokinetic parameters of orally administered metoclopramide.

Method: This randomized, single-blind, two-phase cross-over pharmacokinetic study separated by a 4-week washout period was conducted at a single center in Pakistan. It involved twelve Pakistani healthy male volunteers (nonsmokers) divided into two groups. In the reference phase, each volunteer received a single oral dose of 20 mg metoclopramide (Maxolon 10 mg, GlaxoSmithKline, Pakistan), while in the rifampicin-treated phase, each volunteer received 600 mg rifampicin once daily for 6 days through oral route. On day 6, metoclopramide (20 mg) was administered 2 hours after the last pretreatment dose of rifampicin. The serial blood samples were collected on predetermined time points (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 18 h) and analyzed using a validated HPLC method for the determination of pharmacokinetic parameters, i.e. Cmax, Tmax, and AUC0-∞ of metoclopramide. The whole study was monitored by an unblinded clinician for the purpose of volunteer’s health safety.

Results: All the volunteers participated in the study until the end. Twelve healthy Pakistani males having mean age 26.0 (range 20.6-34.1) years and body mass index 25.1 (range 16.2-31.5) kg/m2 were included in this study after taking written informed consent. Rifampicin significantly (P<0.05) decreased the mean Cmax, AUC0-∞ and T1/2 of metoclopramide by 35%, 68%, and 44%, respectively. The laboratory tests did not reveal any significant change in the biochemical, physical, hematological, or urinalytical values before and after metoclopramide treatment. None of the volunteers complained of any discomfort during the study.

Conclusion: Rifampicin noticeably decreased the concentration of plasma metoclopramide. These results give in vivo confirmation of the CYP3A4 involvement in the metoclopramide metabolism, in addition to CYP2D6. Therefore, metoclopramide pharmacokinetics may be clinically affected by rifampicin and other potent enzyme inducers.

Keywords: Cytochrome 450, cross-over design, metoclopramide, rifampicin, CYP3A4 inducers, pharmacokinetics.

[1]
Kuhlmann, J.; Mück, W. Clinical-pharmacological strategies to assess drug interaction potential during drug development. Drug Saf., 2001, 24(10), 715-725.
[http://dx.doi.org/10.2165/00002018-200124100-00001] [PMID: 11676300]
[2]
Kaukab, I.; Hussain Shah, S.N.; Murtaza, G. Single dose pharmacokinetics of metoclopramide oral tablets utilizing HPLC-UV method. Curr. Pharm. Anal., 2019, 15(7), 703-709.
[http://dx.doi.org/10.2174/1573412914666180425123202]
[3]
Chua, E.W.; Harger, S.P.; Kennedy, M.A. Metoclopramide-induced acute dystonic reactions may be associated with the CYP2D6 poor metaboliser status and pregnancy-related hormonal changes. Front. Pharmacol., 2019, 10, 931-939.
[http://dx.doi.org/10.3389/fphar.2019.00931] [PMID: 31507424]
[4]
Zhou, W.J.; Wei, B.; Cai, F.F.; Yang, M.D.; Chen, X.L.; Chen, Q.L. Therapeutic effect of jianpi decoction combined with chemotherapy on postoperative treatment of colorectal cancer: A systematic review and meta-analysis. World J. Tradit. Chin. Med., 2019, 5, 228-235.
[http://dx.doi.org/10.4103/wjtcm.wjtcm_25_19]
[5]
Feldman, M.; Friedman, L.S.; Brandt, L.J. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 9th ed; Saunders: Philadelphia, 2010.
[6]
Desta, Z.; Wu, G.M.; Morocho, A.M.; Flockhart, D.A. The gastroprokinetic and antiemetic drug metoclopramide is a substrate and inhibitor of cytochrome P450 2D6. Drug Metab. Dispos., 2002, 30(3), 336-343.
[http://dx.doi.org/10.1124/dmd.30.3.336] [PMID: 11854155]
[7]
Yu, J.; Paine, M.J.; Maréchal, J.D.; Kemp, C.A.; Ward, C.J.; Brown, S.; Sutcliffe, M.J.; Roberts, G.C.; Rankin, E.M.; Wolf, C.R. In silico prediction of drug binding to CYP2D6: identification of a new metabolite of metoclopramide. Drug Metab. Dispos., 2006, 34(8), 1386-1392.
[http://dx.doi.org/10.1124/dmd.106.009852] [PMID: 16698891]
[8]
Doran, A.; Obach, R.S.; Smith, B.J.; Hosea, N.A.; Becker, S.; Callegari, E.; Chen, C.; Chen, X.; Choo, E.; Cianfrogna, J.; Cox, L.M.; Gibbs, J.P.; Gibbs, M.A.; Hatch, H.; Hop, C.E.; Kasman, I.N.; Laperle, J.; Liu, J.; Liu, X.; Logman, M.; Maclin, D.; Nedza, F.M.; Nelson, F.; Olson, E.; Rahematpura, S.; Raunig, D.; Rogers, S.; Schmidt, K.; Spracklin, D.K.; Szewc, M.; Troutman, M.; Tseng, E.; Tu, M.; Van Deusen, J.W.; Venkatakrishnan, K.; Walens, G.; Wang, E.Q.; Wong, D.; Yasgar, A.S.; Zhang, C. The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model. Drug Metab. Dispos., 2005, 33(1), 165-174.
[http://dx.doi.org/10.1124/dmd.104.001230] [PMID: 15502009]
[9]
Argikar, U.A.; Gomez, J.; Ung, D.; Parkman, H.P.; Nagar, S. Identification of novel metoclopramide metabolites in humans: in vitro and in vivo studies. Drug Metab. Dispos., 2010, 38(8), 1295-1307.
[http://dx.doi.org/10.1124/dmd.110.033357] [PMID: 20423954]
[10]
Kanebratt, K.P.; Diczfalusy, U.; Bäckström, T.; Sparve, E.; Bredberg, E.; Böttiger, Y.; Andersson, T.B.; Bertilsson, L. Cytochrome P450 induction by rifampicin in healthy subjects: determination using the Karolinska cocktail and the endogenous CYP3A4 marker 4β-hydroxycholesterol. Clin. Pharmacol. Ther., 2008, 84(5), 589-594.
[http://dx.doi.org/10.1038/clpt.2008.132] [PMID: 18650803]
[11]
World Medical Association General Assembly. Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects, 2013, Retrieved from: Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects. Available at:, https://www.wma.net/policies-post/wma-declaration-of-helsinkiethical-principles-for-medical-researchinvolving-human-subjects/.
[12]
nternational Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Guideline for good clinical practice E6, 1996, 1996. Available at:, http://www.ich.org/products/guidelines/efficacy/article/efficacy guidelines.html
[13]
Westphal, J.F. Macrolide - induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin. Br. J. Clin. Pharmacol., 2000, 50(4), 285-295.
[http://dx.doi.org/10.1046/j.1365-2125.2000.00261.x] [PMID: 11012550]
[14]
Akhtar, B.; Ashraf, M.; Javeed, A.; Sharif, A.; Akhtar, M.F.; Saleem, A.; Hamid, I.; Alvi, S.; Murtaza, G. Analgesic, antipyretic and anti-inflammatory activities of Grewia asiatica fruit extracts in albino mice. Acta Pol. Pharm., 2016, 73(4), 983-989.
[PMID: 29648724]
[15]
Saari, T.I.; Grönlund, J.; Hagelberg, N.M.; Neuvonen, M.; Laine, K.; Neuvonen, P.J.; Olkkola, K.T. Effects of itraconazole on the pharmacokinetics and pharmacodynamics of intravenously and orally administered oxycodone. Eur. J. Clin. Pharmacol., 2010, 66(4), 387-397.
[http://dx.doi.org/10.1007/s00228-009-0775-8] [PMID: 20076952]
[16]
Kaukab, I.; Hussain Shah, S.N.; Kharaba, Z.; Murtaza, G.; Saad, A.A.; Ahmad, S. Evaluation of pharmacokinetic interaction of cilostazol with metoclopramide after oral administration in human. Curr. Drug Metab., 2019, 20(11), 924-928.
[http://dx.doi.org/10.2174/1389200220666191105115805] [PMID: 31702486]
[17]
Chan, E.D.; Iseman, M.D. Current medical treatment for tuberculosis. BMJ, 2002, 325(7375), 1282-1286.
[http://dx.doi.org/10.1136/bmj.325.7375.1282] [PMID: 12458250]
[18]
Wang, J.B.; Shi, Z.; Xiao, X.H. Disease-based toxicology on safety assessment strategy and application for herbal and traditional medicines. World J. Tradit. Chin. Med., 2019, 5, 139-144.
[http://dx.doi.org/10.4103/wjtcm.wjtcm_18_19]
[19]
Razzaq, R.; Farzana, K.; Mahmood, S.; Murtaza, G. The analyses of microbiological distribution of street vended vegetables in Multan City, Pakistan for exploring a public health issue. Pak. J. Zool., 2014, 46(4), 1133-1138.
[20]
Niemi, M.; Backman, J.T.; Fromm, M.F.; Neuvonen, P.J.; Kivistö, K.T. Pharmacokinetic interactions with rifampicin : clinical relevance. Clin. Pharmacokinet., 2003, 42(9), 819-850.
[http://dx.doi.org/10.2165/00003088-200342090-00003] [PMID: 12882588]
[21]
Zhang, G.P.; Zhang, H.J.; Chen, T.F.; Hou, H.P.; Su, P.; Gao, Y.H. Screening and identifying hepatotoxic components in Polygoni multiflori Radix and Polygoni multiflori Radix Praeparata. World J. Tradit. Chin. Med., 2019, 5, 173-179.
[http://dx.doi.org/10.4103/wjtcm.wjtcm_29_19]
[22]
Fromm, M.F.; Kauffmann, H.M.; Fritz, P.; Burk, O.; Kroemer, H.K.; Warzok, R.W.; Eichelbaum, M.; Siegmund, W.; Schrenk, D. The effect of rifampin treatment on intestinal expression of human MRP transporters. Am. J. Pathol., 2000, 157(5), 1575-1580.
[http://dx.doi.org/10.1016/S0002-9440(10)64794-3] [PMID: 11073816]
[23]
Hamman, M.A.; Bruce, M.A.; Haehner-Daniels, B.D.; Hall, S.D. The effect of rifampin administration on the disposition of fexofenadine. Clin. Pharmacol. Ther., 2001, 69(3), 114-121.
[http://dx.doi.org/10.1067/mcp.2001.113697] [PMID: 11240975]
[24]
Westphal, K.; Weinbrenner, A.; Zschiesche, M.; Franke, G.; Knoke, M.; Oertel, R.; Fritz, P.; von Richter, O.; Warzok, R.; Hachenberg, T.; Kauffmann, H.M.; Schrenk, D.; Terhaag, B.; Kroemer, H.K.; Siegmund, W. Induction of P-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: a new type of drug/drug interaction. Clin. Pharmacol. Ther., 2000, 68(4), 345-355.
[http://dx.doi.org/10.1067/mcp.2000.109797] [PMID: 11061574]
[25]
Kyrklund, C.; Backman, J.T.; Neuvonen, M.; Neuvonen, P.J. Effect of rifampicin on pravastatin pharmacokinetics in healthy subjects. Br. J. Clin. Pharmacol., 2004, 57(2), 181-187.
[http://dx.doi.org/10.1046/j.1365-2125.2003.01972.x] [PMID: 14748817]
[26]
DuBuske, L.M. The role of P-glycoprotein and organic anion-transporting polypeptides in drug interactions. Drug Saf., 2005, 28(9), 789-801.
[http://dx.doi.org/10.2165/00002018-200528090-00004] [PMID: 16119972]
[27]
Karlgren, M.; Vildhede, A.; Norinder, U.; Wisniewski, J.R.; Kimoto, E.; Lai, Y.; Haglund, U.; Artursson, P. Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J. Med. Chem., 2012, 55(10), 4740-4763.
[http://dx.doi.org/10.1021/jm300212s] [PMID: 22541068]
[28]
Hendrickx, R.; Johansson, J.G.; Lohmann, C.; Jenvert, R.M.; Blomgren, A.; Börjesson, L.; Gustavsson, L. Identification of novel substrates and structure-activity relationship of cellular uptake mediated by human organic cation transporters 1 and 2. J. Med. Chem., 2013, 56(18), 7232-7242.
[http://dx.doi.org/10.1021/jm400966v] [PMID: 23984907]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 21
ISSUE: 4
Year: 2020
Page: [301 - 306]
Pages: 6
DOI: 10.2174/1389200221666200514132654
Price: $65

Article Metrics

PDF: 16
HTML: 1