Inhibition of Human Cytochrome P450 2c8-catalyzed Amodiaquine N-desethylation: Effect of Five Traditionally and Commonly Used Herbs.
BACKGROUND
In Southeast Asia and many parts of the world, herbal products are increasingly used in parallel with modern medicine.


OBJECTIVE
This study aimed to investigate the effects of herbs commonly used in Southeast Asia on activity of cytochrome P450 2C8 (CYP2C8), an important human hepatic enzyme in drug metabolism.


METHODS
The selected herbs, such asEurycoma longifoliaJack (ELJ),Labisia pumila(LP),Echinacea purpurea(EP),Andrographis paniculata(AP), andGinkgo biloba(GB), were subjected to inhibition studies using anin vitroCYP2C8 activity marker, amodiaquine N-desethylase assay. Inhibition parameters, inhibitory concentration 50% (IC50), and Kivalues were determined to study the potency and mode of inhibition.


RESULTS
All herbs inhibited CYP2C8 with the following order of potency: LP > ELJ > GB > AP > EP. LP and ELJ inhibited potently at Ki's of 2 and 4 times the Kiof quercetin, the positive control. The inhibition by LP was uncompetitive in nature as compared to competitive or mixed type inhibition observed with other herbs. GB exhibited moderate inhibitory effect at a Ki6 times larger than quercetin Ki. AP and EP, on the other hand, showed only weak inhibition.


CONCLUSIONS
The herbs we chose represented the more commonly used herbs in Southeast Asia where collision of tradition and modernization in healthcare, if not properly managed, may lead to therapeutic misadventures. We conclude that concurrent consumption of some herbs, in particular, LP and ELJ, may have relevance in drug-herb interactions via CYP2C8 inhibitionin vivo.


CONCLUSIONS
Herbs are increasingly used in parallel with modern medicines nowadays. In this study five commonly used herbs in Southeast Asia region, ELJ, LP, EP, AP and GB, were investigated for theirin vitroinhibitory potency on CYP2C8, an important drug-metaboliz-ing human hepatic enzyme. All herbs inhibited CYP2C8 activity marker, amodiaquine N-desethylation, with potency order of LP > ELJ > GB >AP > EP. LP, ELJ and GB exhibited Kivalues of 2, 4 and 6 times the Kiof quercetin, the positive control, indicating potent to moderate degree of enzyme inhibition. AP and EP, on the other hand, showed only weak inhibition. In summary, concurrent consumption of some herbs especially LP and ELJ may have relevance in drug-herb interactions via CYP2C8 inhibitionin vivo.Abbreviations Used: AQ: Amodiaquine, AP:Andrographis paniculata, CYP: Cytochrome P450, DEAQ: Desethylamodiaquine, EP:Echinacea purpurea, ELJ:Eurycoma longifolia Jack, GB:Ginkgo biloba, Ki: Inhibition constant, LP:Labisia pumila, Vmax: Maximal velocity, Km: Michaelis-Menten constant.
Pharmacogenetics Research Group, Institute for Research in Molecular Medicine, Universiti Sains, Malaysia.
Yasotha Devi
YD
Muthiah
School of Pharmacy, Monash University, 47500 Bandar Sunway, Selangor, Malaysia.
Chin Eng
CE
Ong
Department of Pharmacology, School of Medical Sciences, Universiti Sains, 16150 Kubang Kerian, Kelantan, Malaysia.
Siti Amrah
SA
Sulaiman
Centre of Excellence for Research in AIDS, Universiti Malaya, 59990 Kuala Lumpur, Malaysia.
Rusli
R
Ismail
Cytochrome P450; cytochrome P450 2C8; drug-herb interaction; inhibition
J Pharmacol Exp Ther. 2002 Feb;300(2):399-407
11805197
Chem Biol Interact. 2009 May 15;179(2-3):247-55
19041297
Chem Res Toxicol. 2006 Feb;19(2):279-87
16485904
Planta Med. 2003 Dec;69(12):1075-9
14750020
Biol Pharm Bull. 2009 Apr;32(4):671-6
19336903
J Ethnopharmacol. 2004 Jun;92(2-3):291-5
15138014
Bioorg Med Chem. 2004 Feb 1;12(3):537-44
14738962
Clin Pharmacol Ther. 2003 Oct;74(4):326-33
14534519
Arterioscler Thromb Vasc Biol. 2003 Sep 1;23(9):1559-66
12893683
Drug Metab Dispos. 2002 Nov;30(11):1153-7
12386118
Arch Pharm Res. 1997 Dec;20(6):656-8
18982276
Biochem Pharmacol. 1999 Oct 1;58(7):1201-8
10484078
Food Chem. 2011 Aug 1;127(3):1186-92
25214112
J Nat Med. 2011 Jul;65(3-4):440-7
21365364
Clin Pharmacol Ther. 2005 May;77(5):341-52
15900280
J Ethnopharmacol. 2006 May 24;105(3):464-7
16406417
Arch Biochem Biophys. 1995 Jul 10;320(2):380-9
7625847
J Ethnopharmacol. 1995 Dec 15;49(3):171-5
8824743
J Ethnopharmacol. 2004 Jun;92(2-3):223-7
15138004
Life Sci. 2004 Jan 9;74(8):935-68
14672753
Clin Pharmacol Ther. 2004 Jan;75(1):89-100
14749695
Phytomedicine. 2006 Jan;13(1-2):67-73
16360935
Am J Ther. 2006 Jan-Feb;13(1):24-31
16428919
Drug Saf. 2005;28(5):387-400
15853441
Planta Med. 2010 Mar;76(4):378-85
19790031
Acta Pharmacol Sin. 2004 Oct;25(10):1306-11
15456532
Molecules. 2011 May 27;16(6):4438-50
21623314
Arch Pharm Res. 1998 Dec;21(6):779-81
9868556
Phytomedicine. 2000 Jul;7(4):273-82
10969720
Biol Pharm Bull. 2002 Sep;25(9):1169-74
12230111
Biol Pharm Bull. 2003 Sep;26(9):1315-20
12951478
Jpn J Pharmacol. 2002 Dec;90(4):345-51
12501011
J Clin Pharmacol. 2006 Mar;46(3):337-44
16490810
Arch Biochem Biophys. 1993 Aug 15;305(1):123-31
8342945
Life Sci. 2002 Apr 26;70(23 ):2783-92
12269382
Basic Clin Pharmacol Toxicol. 2007 Apr;100(4):269-72
17371531