Theranostics Meets Traditional Chinese Medicine

Miao Hu; Lan Fan; Hong-Hao Zhou; Brian Tomlinson

Expert Rev Mol Diagn. 2012;12(8):815-830.

Abstract and Introduction

Abstract

Herbal medicines including traditional Chinese medicine are becoming increasingly more popular worldwide. However, there is considerable potential for interaction between herbal components and drugs, as all herbal medicines contain a combination of potentially biologically active compounds possessing various inherent pharmacological activities, and the components of herbal products consumed are eliminated from the body by the same mechanisms that remove drugs. Indeed, many so-called conventional drugs are derived from plant sources. This article provides an update on the mechanisms and evidence of drug–herb interactions (DHIs) and genetic influences on DHIs. The rational prediction of clinically important DHIs is also discussed. Individualized and targeted drug therapy could be achieved by identifying the population most likely to be helped or harmed by drug–herb coadministration.

Introduction

Herbal medicines have long been used for a variety of ailments in Asian countries and have become more popular worldwide over the last two decades.^[1,2] It has been reported by the WHO that approximately 70% of the world's population currently uses medicinal herbs as complementary or alternative medicine.^[1,3] There is a general belief by the public that herbal medicines are safe because of their natural origin, and consumers often take these products without consulting or informing their regular healthcare providers.^[4] However, all herbal medicines are actually a combination of potentially biologically active compounds possessing various inherent pharmacological activities, and as the metabolism of these compounds usually occurs by the same mechanisms as that of drugs, there is considerable potential for the interaction between herbal components and drugs.^[5] Herbal supplements are often used concomitantly with conventional drugs, especially in the elderly or those with chronic disease who are likely to be treated with multiple drugs, raising the increased risk of drug–herb interactions (DHIs) with potentially serious consequences, particularly for those drugs with very narrow therapeutic indices.^[2,6–8] This article aims to provide an update on the mechanisms and evidence of DHIs and discusses the rational prediction of clinically important DHIs.

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Next Section

Abstract and Introduction
Mechanism of DHIs
Selective Clinical Evidence of DHIs
Theranostics Applications in Predicting DHIs
Theranostics Approaches to Predicting DHIs
Expert Commentary
Five-year View
References
Sidebar

Table 1. Effects of herbs on drug-metabolizing enzymes and transporters.
Herbs	In vitro	Animal	Clinical	Ref.
Black cohosh (Actaea racemosa)	↓ 1A2, 2D6, 2C9 and 3A4	↑ CYP3A11	↔	[9,134,135]
Danshen (Salvia miltiorrhiza)	↓ CYP1A2, 2C9, 2D6 and 3A4	↓ CYP2C9	↓ CYP2C9	[12,87,136,137]
Dong quai (Angelica dahurica)	↓ CYP1A1/2, 2C9, 2D6, 2D15, 2E1 and 3A	↓ CYP2C, CYP3A and CYP2D1		[12,138–141]
Echinacea (Echinacea purpurea)	↓ CYP2C9, 2C19, 2D6, 3A4, P-gp and SLCO1B1		↓ CYP3A or CYP1A2	[9,34,142,143]
Garlic (Allium sativum)	↓ CYP2C9, 2C19, 3A and P-gp	↑ CYP1A1, 2B1 and 3A1; ↓ CYP2E1	↓ CYP2E1; ↑ P-gp	[9]
Ginkgo (Ginkgo biloba)	↓ CYP1A2, 2B6 2C9, 2E1, 3A4 and UGT; or ↑CYP450 enzymes, transporters and UGT1A1	↑ CYP1A1/2, 2B, 2C9, 2E1 and 3A	↑ CYP2C9, 2C19 and 3A4	[12,33,35,40,42–46,144]
Ginseng (Panax ginseng)	↓ CYP2C9, 2C19, 3A4, 2D6 and P-gp; or ↑ P-gp	↑ P-gp	↔	[12,68,145–147]
Grapefruit juice (Citrus paradise)	↓ intestinal CYP3A4, P-gp and SLCOs	↓ CYP3A4 and P-gp	↓ CYP3A4 and SLCO2B1	[12,13,20–22,70,71,110]
Goldenseal (Hydrastis canadensis)	↓ CYP2C9, 2C19, 3A4 and 2D6		↓ CYP2D6 and 3A4/5	[9,109,148,149]
Green tea (Camellia sinensis)	↓ CYP2C9, 2D6 and 3A4		↓ CYP3A4	[12,57,150]
Milk thistle (Sylibum marianum)	↓ CYP3A4, 2C9, 2E1, 2D6, 2C19, 1A2 and 2A6, P-gp, UGT1A1	↓ CYP3A, 2C9 and P-gp	↑ CYP3A4 and P-gp; ↓ CYP2C9 and P-gp	[151–158]
St John's wort (Hypericum perforatum)	↑ CYP3A4, 2C9 and P-gp		↑ CYP3A4 and P-gp	[24–28]

↑: Activation or induction; ↓: Inhibition; ↔: No effect.

Table 2. Effect of genetic polymorphisms on herb–drug interactions.
Herbs	Drugs	Effect of genetic polymorphisms on herb–drug interactions	Effect of genetic polymorphisms on the activity/protein/mRNA levels of the drug-metabolizing enzymes and drug transporters	Ref.
Baicalin	Bupropion	Mean changes in AUC ratio tended to be lower for subjects with CYP2B66/6 genotype compared with those with CYP2B61/1 genotype following baicalin use, indicating baicalin induction of CYP2B6-catalyzed bupropion hydroxylation	Reduced with the variant allele	[159]
	Rosuvastatin	The AUC_0–∞ of rosuvastatin decreased by approximately 42, 24 and 1.8% in SLCO1B1 1b1b, 1b15 and 1515 carriers, respectively	Reduced with the variant allele	[160]
Cranberry juice	Warfarin	Cranberry significantly increased the area under the INR–time curve by 30% when administered with warfarin without altering PKs or plasma protein binding of S- or R-warfarin. Subjects with one or two copies of the variant alleles for VKORC1 had a significant reduction in S-warfarin EC₅₀ (concentration of S-warfarin that produces 50% inhibition of prothrombin complex activity) when warfarin was coadministered with cranberry juice extract	Increased sensitivity to warfarin with the VKORC1 variant allele	[161]
Echinacea	Dextromethorphan	The AUC of dextromethorphan was increased (42%) in CYP2D6 PMs but not in extensive metabolizers	Reduced with the variant allele	[143]
Garlic	Warfarin	Coadministration of garlic did not significantly alter warfarin pharmacokinetics or pharmacodynamics. However, subjects with the VKORC1 wild-type genotype showed an increase in the S-warfarin EC₅₀ when warfarin was administered with garlic	Increased sensitivity to warfarin with the VKORC1 variant allele	[161]
Grapefruit juice	Ebastine	Homozygous wild-types of ABCB1 3435C>T but not the other genotypes showed a significant decrease in the active metabolite carebastine urinary excretion after grapefruit juice	Reduced with the variant allele	[162]
	Felodipine	Grapefruit juice treatment significantly increased AUC_{0–12 h} of felodipine by 100% which was independent of CYP3A5*3 genotype	Reduced with the variant allele	[163]
	Lansoprazole	Grapefruit juice treatment significantly increased total AUC of lansoprazole in CYP2C19 PMs (2, 3), and the total AUC ratio of lansoprazole sulfone/lansoprazole was significantly decreased in CYP2C19 homozygous extensive metabolizers (1/1)	Reduced with the variant allele	[164]
	Lansoprazole	No effect of grapefruit juice on PK of lansoprazole in all CYP2C19 genotypes	Reduced with the variant allele	[165]
Ginkgo	Omeprazole	Ginkgo enhanced omeprazole hydroxylation in a CYP2C19 genotype-dependent manner. The decrease was greater in CYP2C19 PMs (2, 3) than extensive metabolizers	Reduced with the variant allele	[42]
St John's wort	Gliclazide	Treatment with St John's wort significantly increased the apparent clearance of gliclazide which was independent of CYP2C9 genotype	Reduced with the variant allele	[166]
	Mephenytoin	St John's wort treatment significantly increased phenytoin clearance in CYP2C19 extensive metabolizers but not in PMs (2, 3)	Reduced with the variant allele	[167]
	Nifedipine	After administration of St John's wort, the AUC_0–∞ of nifedipine and dehydronifedipine decreased by 42.4 and 20.2% in PXR H1/H2; 47.9 and 33.0% in H2/H2; whereas for the H1/H1, the AUC_0–∞ of nifedipine decreased 29.0%, but the AUC_0–∞ of dehydronifedipine increased by 106.7%	Reduced basal transcriptional activity, but stronger induced transcriptional activity on CYP3A4 with H1/H1 compared with H1/H2 and H2/H2	[168]
	Omeprazole	St John's wort decreased the plasma concentrations of omeprazole in a CYP2C19 genotype-dependent manner	Reduced with the variant allele	[169]
	Repaglinide	No effect of St John's wort on PK of repaglinide in all SLCO1B1 genotypes	Reduced with the variant allele	[170]
	Talinolol	Subjects harboring the ABCB1 haplotype comprising 1236C>T, 2677G>T/A and 3435C>T polymorphisms had lower intestinal MDR1 mRNA levels and showed an attenuated inductive response to St John's wort as assessed by talinolol disposition	Reduced with the variant allele	[66]
	Voriconazole	The AUC of voriconazole was decreased by 59% with St John's wort treatment, with a 144% increase in oral clearance o f voriconazole. The baseline apparent oral clearance of voriconazole and the absolute increase in apparent oral clearance were smaller in CYP2C192 carriers than those with CYP2C19*1/1 genotype	Reduced with the variant allele	[171]

AUC: Area under the curve; CYP: Cytochrome P450; INR: International normalized ratio; PK: Pharmacokinetic; PM: Poor metabolizer; PXR: Pregnane X receptor.