Although there are inherent and recognized limitations of in vitro screening methodologies to assess conventional drug-drug interactions (DDIs) per industry guidelines and those adopted by independent laboratories, further limitations are being appreciated which are unique to the evaluation of botanical products and potential DDIs in which they may participate. Among the larger issues faced are the uncertainty in assigning hepatic concentrations of multiple constituents and their potential metabolites, accounting for oral bioavailability, distribution, first-pass metabolism and active metabolites. Furthermore, the wide variability in the chemical composition of commercially available botanical supplement formulations continues to be a major concern, and manufacturing standards or enforcement thereof is essentially nonexistent in most countries. Differing formulations, unspecified product excipients, administration and absorption of the therapeutic ingredient(s) of a standardized dosage form, the very presence and/or concentration of one or more phytoconstituents within a supplement are typically unknown and nontarget entities. A further issue is the absence of authentic analytical standards, and the inability to accurately screen the entities as mixtures to even approximate typical scenarios, which may occur following the ingestion of dietary supplements, adds additional layers of complexity to experimental design and difficulty in interpreting experimental results. Multiple challenges exist in experimental methodologies employed in performing in vitro research with conventional pharmaceuticals and those unique to botanical extracts. These obstacles prevent the investigators from effectively utilizing high-throughput models to accomplish more than essentially “flag” suspected sources of drug interactions which must be further evaluated in vivo, at present, in order to confirm clinical significance. This review is intended to discuss the problems and challenges in evaluating botanical-drug interactions using in vitro methodologies.
Key words
botanical -
interaction -
in vitro
-
in vivo
-
metabolism
References
1 Newman DJ, Cragg GM. Natural products as sources of new drugs over the last 25 years. J Nat Prod 2007; 70: 461-477
3 Markowitz JS, von Moltke LL, Donovan JL. Predicting interactions between conventional medications and botanical products on the basis of in vitro investigations. Mol Nutr Food Res 2008; 52: 747-754
4 Greenblatt DJ, von Moltke LL, Harmatz JS, Chen G, Weemhoff JL, Jen C, Kelley CJ, LeDuc BW, Zinny MA. Time course of recovery of cytochrome p 450 3A function after single doses of grapefruit juice. Clin Pharmacol Ther 2003; 74: 121-129
5 Li P, Callery PS, Gan LS, Balani SK. Esterase inhibition by grapefruit juice flavonoids leading to a new drug interaction. Drug Metab Dispos 2007; 35: 1203-1208
6 Li P, Callery PS, Gan LS, Balani SK. Esterase inhibition attribute of grapefruit juice leading to a new drug interaction. Drug Metab Dispos 2007; 35: 1023-1031
7 Liu R, Tam TW, Mao J, Saleem A, Krantis A, Arnason JT, Foster BC. The effect of natural health products and traditional medicines on the activity of human hepatic microsomal-mediated metabolism of oseltamivir. J Pharm Pharm Sci 2010; 13: 43-55
13 von Moltke LL, Greenblatt DJ, Schmider J, Wright CE, Harmatz JS, Shader RI.
In vitro approaches to predicting drug interactions in vivo
. Biochem Pharmacol 1998; 55: 113-222
14 Pelkonen O, Turpeinen M, Uusitalo J, Rautio A, Raunio H. Prediction of drug metabolism and interactions on the basis of in vitro investigations. J Basic Clin Pharmacol Toxicol 2005; 96: 167-175
18 Li Y, Revalde JL, Reid G, Paxton JW. Interactions of dietary phytochemicals with ABC transporters: possible implications for drug disposition and multidrug resistance in cancer. Drug Metab Rev 2010; 42: 590-611
21 Masimirembwa CM, Thompson R, Andersson TB.
In vitro high throughput screening of compounds for favorable metabolic properties in drug discovery. Comb Chem High Throughput Screen 2001; 4: 245-263
22 Kosugi Y, Hirabayashi H, Igari T, Fujioka Y, Hara Y, Okuda T, Moriwaki T. Evaluation of cytochrome P450-mediated drug-drug interactions based on the strategies recommended by regulatory authorities. Xenobiotica 2012; 42: 127-138
25 Hedman A, Meijer DK. The stereoisomers quinine and quinidine exhibit a marked stereoselectivity in the inhibition of hepatobiliary transport of cardiac glycosides. J Hepatol 1998; 28: 240-249
26 Ai C, Li Y, Wang Y, Chen Y, Yang L. Insight into the effects of chiral isomers quinidine and quinine on CYP2D6 inhibition. Bioorg Med Chem Lett 2009; 19: 803-806
27 Kroon PA, Clifford MN, Crozier A, Day AJ, Donovan JL, Manach C, Williamson G. How should we assess the effects of exposure to dietary polyphenols in vitro?. Am J Clin Nutr 2004; 80: 15-21
29 Donovan JL, DeVane CL, Boulton D, Dodd S, Markowitz JS. Dietary levels of quinine in tonic water do not inhibit CYP2D6 in vivo
. Food Chem Toxicol 2003; 41: 1199-1201
30 Sridar C, Goosen TC, Kent UM, Williams JA, Hollenberg PF. Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases. Drug Metab Dispos 2004; 32: 587-594
32 Beckmann-Knopp S, Rietbrock S, Weyhenmeyer R, Böcker RH, Beckurts KT, Lang W, Hunz M, Fuhr U. Inhibitory effects of silibinin on cytochrome P-450 enzymes in human liver microsomes. Pharmacol Toxicol 2000; 86: 250-256
33 Zuber R, Modriansky M, Dvorák Z, Rohovský P, Ulrichová J, Simánek V, Anzenbacher P. Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities. Phytother Res 2002; 16: 632-638
34 Zhang S, Morris ME. Effect of the flavonoids biochanin A and silymarin on the P-glycoprotein-mediated transport of digoxin and vinblastine in human intestinal Caco-2 cells. Pharm Res 2003; 20: 1184-1191
35 Zhang S, Morris ME. Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P-glycoprotein-mediated transport. J Pharmacol Exp Ther 2003; 304: 1258-1267
36 Zhao J, Agarwal R. Tissue distribution of silibinin, the major active constituent of silymarin, in mice and its association with enhancement of phase II enzymes: implications in cancer chemoprevention. Carcinogenesis 1999; 20: 2101-2108
37 Piscitelli SC, Formentini E, Burstein AH, Alfaro R, Jagannatha S, Falloon J. Effect of milk thistle on the pharmacokinetics of indinavir in healthy volunteers. Pharmacotherapy 2002; 22: 551-556
38 DiCenzo R, Shelton M, Jordan K, Koval C, Forrest A, Reichman R, Morse G. Coadministration of milk thistle and indinavir in healthy subjects. Pharmacotherapy 2003; 23: 866-870
39 Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Carrier J, Khan IA, Edwards DJ, Shah A.
In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto. Clin Pharmacol Ther 2004; 76: 428-440
41 Wu JW, Lin LC, Hung SC, Chi CW, Tsai TH. Analysis of silibinin in rat plasma and bile for hepatobiliary excretion and oral bioavailability application. J Pharm Biomed Anal 2007; 45: 635-641
42 Wen Z, Dumas TE, Schrieber SJ, Hawke RL, Fried MW, Smith PC. Pharmacokinetics and metabolic profile of free, conjugated, and total silymarin flavonolignans in human plasma after oral administration of milk thistle extract. Drug Metab Dispos 2008; 36: 65-72
43 Imai T, Imoto M, Sakamoto H, Hashimoto M. Identification of esterases expressed in Caco-2 cells and effects of their hydrolyzing activity in predicting human intestinal absorption. Drug Metab Dispos 2005; 33: 1185-1190
45 Chen ML, Straughn AB, Sadrieh N, Meyer M, Faustino PJ, Ciavarella AB, Meibohm B, Yates CR, Hussain AS. A modern view of excipient effects on bioequivalence: case study of sorbitol. Pharm Res 2007; 24: 73-80
46 Xin GZ, Qi LW, Shi ZQ, Li P, Hao HP, Wang GJ, Shang J. Strategies for integral metabolism profile of multiple compounds in herbal medicines: pharmacokinetics, metabolites characterization and metabolic interactions. Curr Drug Metab 2011; 12: 809-817
