Drug-Herb Interactions: Eliminating Toxicity with Hard Drug Design

Abstract

By searching the literatures, it was found that a total of 32 drugs interacting with herbal medicines in humans. These drugs mainly include anticoagulants (warfarin, aspirin and phenprocoumon), sedatives and antidepressants (midazolam, alprazolam and amitriptyline), oral contraceptives, anti-HIV agents (indinavir, ritonavir and saquinavir), cardiovascular drug (digoxin), immunosuppressants (cyclosporine and tacrolimus) and anticancer drugs (imatinib and irinotecan). Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (PgP) and many of which have narrow therapeutic indices. However, several drugs including acetaminophen, carbamazepine, mycophenolic acid, and pravastatin did not interact with herbs. Both pharmacokinetic (e.g. induction of hepatic CYPs and intestinal PgP) and/or pharmacodynamic mechanisms (e.g. synergistic or antagonistic interaction on the same drug target) may be involved in drug-herb interactions, leading of altered drug clearance, response and toxicity. Toxicity arising from drug-herb interactions may be minor, moderate, or even fatal, depending on a number of factors associated with the patients, herbs and drugs. Predicting drug-herb interactions, timely identification of drugs that interact with herbs, and therapeutic drug monitoring may minimize toxic drug-herb interactions. It is likely to predict pharmacokinetic herb-drug interactions by following the pharmacokinetic principles and using proper models that are used for predicting drug-drug interactions. Identification of drugs that interact with herbs can be incorporated into the early stages of drug development. A fourth approach for circumventing toxicity arising from drug-herb interactions is proper design of drugs with minimal potential for herbal interaction. So-called "hard drugs" that are not metabolized by CYPs and not transported by PgP are believed not to interact with herbs due to their unique pharmacokinetic properties. More studies are needed and new approached are required to minimize toxicity arising from drug-herb interactions.

A Comparison of Pharmacokinetics between Humans and Monkeys

“…We allocated the 13 drugs into five categories (Type A-E), according to their pharmacokinetic properties in humans, as follows: membrane permeability, P450 isozyme selectivity, and P-gp affinity (Yu, 1999;Kivist et al, 2004;Yang et al, 2006) (Table 1).…”

The safe usage of herbal medicines: counterindications, cross-reactivity and toxicity

“…In other cases, the metabolism, distribution and/or excretion of a compound may be affected. The clinical importance arises when the pharmacokinetic properties (such as Tmax, Cmax or AUC) of these agents is modified through drugherb interactions, 62 such that drug efficacy and ultimate toxicity is subsequently affected. This occurs more frequently for drugs possessing narrow therapeutic windows, such as digoxin.…”

Can we Avoid Unfavourable Clinical Herb-Drug Interactions?

“…Because the pharmacokinetics and/or pharmacodynamics of the drug may be altered by combination with herbal remedies, severe and perhaps even life-threatening adverse reactions may occur in clinical practice. Due to the clinical significance of herbal interactions with conventional drugs, it is important to identify clinically important herb-drug interactions and the information is useful for providing warning and proper professional advices to patients in clinical practice or consumers of herbal medicines [9].…”

“…Thus, timely identification of drugs capable of interacting with herbal medicines is important to remind clinicians and drug scientists [9]. Existing knowledge advises us that many herbal medicines should not be taken at the same time with many other drugs that have a narrow therapeutic index.…”

“…The critical examination of interactions between herbal medicines and drugs requires the ability to accurately determine not only the presence of altered metabolism and transport but also the ability to quantitate the extent of the interaction and clinical consequences in humans. practice and herb-drug interactions have important clinical and toxicological implications, a proper design of drugs that have minimal potential for herbal interaction has important implications in drug development [9]. If the drugs have to be used in combination with herbal medicines, in some instances rational use of such drugs becomes necessary, including the use of a safe drug combination regimen, dose adjustment, and discontinuation of therapy when toxic herb-drug interactions occur.…”