A regulatory science viewpoint on botanical–drug interactions

Abstract

There is a continued predisposition of concurrent use of drugs and botanical products. Consumers often self-administer botanical products without informing their health care providers. The perceived safety of botanical products with lack of knowledge of the interaction potential poses a challenge for providers and both efficacy and safety concerns for patients. Botanical-drug combinations can produce untoward effects when botanical constituents modulate drug metabolizing enzymes and/or transporters impacting the systemic or tissue exposure of concomitant drugs. Examples of pertinent scientific literature evaluating the interaction potential of commonly used botanicals in the US are discussed. Current methodologies that can be applied to advance our efforts in predicting drug interaction liability is presented. This review also highlights the regulatory science viewpoint on botanical-drug interactions and labeling implications.

Pharmacokinetic Interactions between Cardiovascular Medicines and Plant Products

“…Induction or inhibition of the CYP450 activity is one of the most important pharmacokinetic interaction. CYP450 is a family of enzymes involved in the oxidative metabolism (phase I) of most drugs in clinical practice [5]. The major drug-metabolising enzymes are CYP1A2, CYP2C8 /2C9/2C19, CYP2D6, and CYP3A4.…”

“…The induction of metabolic enzymes results in an increase in systemic clearance and in therapeutic failure. Metabolic enzymes inhibition may manifest clinically by an increase in systemic exposure of drug with phenomena of overdosing and increased toxicity [5]. CYPs induction is slow and a regulated process that takes time to achieve a higher steady-state enzyme levels, while the inhibition of CYPs is an almost immediate response.…”

“…Enzymatic inhibition can be classified as reversible (competitive and non-competitive) and timedependent. Unlike reversible inhibition, time-dependent inhibition may persist even after the disappearance of the agent causing the interaction because the recovery of enzyme activity requires de novo synthesis of proteins [5].…”

“…They are involved in oral and kidney absorption and hepatobiliary availability of drugs. From a clinical point of view, transporters modulation may be manifested as either an increase or decrease in systemic availability depending on the transport direction (efflux/influx) and the location (apical/canalicular, basolateral/sinusoidal) [5]. ABC binding cassette transporters, OATPs, OATs and OCTs are the major carriers involved in the efflux and influx of cardiovascular drugs [13].…”

“…The effects are more pronounced with the CCBs that have lower bioavailability (nimodipine, nisoldipine). Thus, intake of grapefruit juice (200-600 mL qd or bid for 2-3 days), increases the exposure to nisoldipine by 85% [5]. A single glass (200-250 mL) of regular-strength grapefruit juice can produce a several-fold increase in AUC and max of felodipine, although with considerable interindividual variability (Table 1).…”