Co-consuming green tea with raloxifene decreases raloxifene systemic exposure in healthy adult participants.

Green tea is a popular beverage worldwide. The abundant green tea catechin (-)-epigallocatechin gallate (EGCG) is a potent in vitro inhibitor of intestinal UDP-glucuronosyltransferase (UGT) activity (Ki ~2 µM). Co-consuming green tea with intestinal UGT drug substrates, including raloxifene, could increase systemic drug exposure. The effects of a well-characterized green tea on the pharmacokinetics of raloxifene, raloxifene 4'-glucuronide, and raloxifene 6-glucuronide were evaluated in 16 healthy adults via a three-arm crossover, fixed-sequence study. Raloxifene (60 mg) was administered orally with water (baseline), with green tea for 1 day (acute), and on the fifth day after daily green tea administration for 4 days (chronic). Unexpectedly, green tea decreased the geometric mean green tea/baseline raloxifene AUC0-96h ratio to ~0.60 after both acute and chronic administration, which is below the predefined no-effect range (0.75-1.33). Lack of change in terminal half-life and glucuronide-to-raloxifene ratios indicated the predominant mechanism was not inhibition of intestinal UGT. One potential mechanism includes inhibition of intestinal transport. Using established transfected cell systems, a green tea extract normalized to EGCG inhibited 10 of 16 transporters tested (IC50 , 0.37-12 µM). Another potential mechanism, interruption by green tea of gut microbe-mediated raloxifene reabsorption, prompted a follow-up exploratory clinical study to evaluate the potential for a green tea-gut microbiota-drug interaction. No clear mechanisms were identified. Overall, results highlight that improvements in current models and methods used to predict UGT-mediated drug interactions are needed. Informing patients about the risk of co-consuming green tea with raloxifene may be considered.

An Integrative Approach to Elucidate Mechanisms Underlying the Pharmacokinetic Goldenseal-Midazolam Interaction: Application of In Vitro Assays and Physiologically Based Pharmacokinetic Models to Understand Clinical Observations.

The natural product goldenseal is a clinical inhibitor of CYP3A activity, as evidenced by a 40%-60% increase in midazolam area under the plasma concentration versus time curve (AUC) after coadministration with goldenseal. The predominant goldenseal alkaloids berberine and (-)-ß-hydrastine were previously identified as time-dependent CYP3A inhibitors using human liver microsomes. Whether these alkaloids contribute to the clinical interaction, as well as the primary anatomic site (hepatic vs. intestinal) and mode of CYP3A inhibition (reversible vs. time-dependent), remain uncharacterized. The objective of this study was to mechanistically assess the pharmacokinetic goldenseal-midazolam interaction using an integrated in vitro-in vivo-in silico approach. Using human intestinal microsomes, (-)-ß-hydrastine was a more potent time-dependent inhibitor of midazolam 1'-hydroxylation than berberine (KI and kinact: 8.48 µM and 0.041 minutes-1, respectively, vs. >250 µM and ∼0.06 minutes-1, respectively). Both the AUC and Cmax of midazolam increased by 40%-60% after acute (single 3-g dose) and chronic (1 g thrice daily × 6 days) goldenseal administration to healthy adults. These increases, coupled with a modest or no increase (≤23%) in half-life, suggested that goldenseal primarily inhibited intestinal CYP3A. A physiologically based pharmacokinetic interaction model incorporating berberine and (-)-ß-hydrastine successfully predicted the goldenseal-midazolam interaction to within 20% of that observed after both chronic and acute goldenseal administration. Simulations implicated (-)-ß-hydrastine as the major alkaloid precipitating the interaction, primarily via time-dependent inhibition of intestinal CYP3A, after chronic and acute goldenseal exposure. Results highlight the potential interplay between time-dependent and reversible inhibition of intestinal CYP3A as the mechanism underlying natural product-drug interactions, even after acute exposure to the precipitant. SIGNIFICANCE STATEMENT: Natural products can alter the pharmacokinetics of an object drug, potentially resulting in increased off-target effects or decreased efficacy of the drug. The objective of this work was to evaluate fundamental mechanisms underlying the clinically observed goldenseal-midazolam interaction. Results support the use of an integrated approach involving established in vitro assays, clinical evaluation, and physiologically based pharmacokinetic modeling to elucidate the complex interplay between multiple phytoconstituents and various pharmacokinetic processes driving a drug interaction.

Translating Kratom-Drug Interactions: From Bedside to Bench and Back.

Kratom is a botanical natural product belonging to the coffee family, with stimulant effects at low doses and opioid-like effects at higher doses. During the last two decades, kratom has been purported as a safer alternative to pharmaceutical and illicit drugs to self-manage pain and opioid withdrawal symptoms. Kratom alkaloids, typically mitragynine, have been detected in biologic samples from overdose deaths. These deaths are often observed in combination with other drugs and are suspected to result from polyintoxications. This review focuses on the potential for kratom to precipitate pharmacokinetic interactions with object drugs involved in these reported polyintoxications. The legal status, chemistry, pharmacology, and toxicology are also summarized. The aggregate in vitro and clinical data identified kratom and select kratom alkaloids as modulators of cytochrome P450 (P450) enzyme activity, notably as inhibitors of CYP2D6 and CYP3A, as well as P-glycoprotein-mediated efflux activity. These inhibitory effects could increase the systemic exposure to co-consumed object drugs, which may lead to adverse effects. Collectively, the evidence to date warrants further evaluation of potential kratom-drug interactions using an iterative approach involving additional mechanistic in vitro studies, well designed clinical studies, and physiologically based pharmacokinetic modeling and simulation. This critical information is needed to fill knowledge gaps regarding the safe and effective use of kratom, thereby addressing ongoing public health concerns. SIGNIFICANCE STATEMENT: The botanical kratom is increasingly used to self-manage pain and opioid withdrawal symptoms due to having opioid-like effects. The legal status, chemistry, pharmacology, toxicology, and drug interaction potential of kratom are reviewed. Kratom-associated polyintoxications and in vitro-in vivo extrapolations suggest that kratom can precipitate pharmacokinetic drug interactions by inhibiting CYP2D6, CYP3A, and P-glycoprotein. An iterative approach that includes clinical studies and physiologically based pharmacokinetic modeling and simulation is recommended for further evaluation of potential unwanted kratom-drug interactions.

Clinical Assessment of the Drug Interaction Potential of the Psychotropic Natural Product Kratom.

Oral formulations prepared from the leaves of the kratom (Mitragyna speciosa) plant are increasingly used for their opioid-like effects to self-manage opioid withdrawal and pain. Calls to US poison centers involving kratom exposures increased >50-fold from 2011-2017, one-third of which reported concomitant use of kratom with drugs of abuse. Many of these drugs are eliminated primarily via cytochrome P450 (CYP) 3A and CYP2D6, raising concerns for potential adverse pharmacokinetic kratom-drug interactions. The impact of a single low dose of kratom tea (2 g) on the pharmacokinetics of the CYP3A probe midazolam (2.5 mg) and CYP2D6 probe dextromethorphan (30 mg) were assessed in 12 healthy adult participants after oral administration. Kratom showed no effect on dextromethorphan area under the plasma concentration time-curve (AUC) and maximum concentration (Cmax ; geometric mean ratio (90% confidence interval) 0.99 (0.83-1.19) and 0.96 (0.78-1.19), respectively) but a modest increase in midazolam AUC and Cmax (1.39 (1.23-1.57) and 1.50 (1.32-1.70), respectively). Lack of change in midazolam half-life (1.07 (0.98-1.17)) suggested that kratom primarily inhibited intestinal CYP3A. This inference was further supported by a physiologically based pharmacokinetic drug interaction model using the abundant alkaloid mitragynine, a relatively potent CYP3A time-dependent inhibitor in vitro (KI , ~4 µM; kinact , ~0.07 min-1 ). This work is the first to clinically evaluate the pharmacokinetic drug interaction potential of kratom. Co-consuming kratom with certain drugs extensively metabolized by CYP3A may precipitate serious interactions. These data fill critical knowledge gaps about the safe use of this increasingly popular natural product, thereby addressing ongoing public health concerns.

Clinical Pharmacokinetic Assessment of Kratom (Mitragyna speciosa), a Botanical Product with Opioid-like Effects, in Healthy Adult Participants.

Increasing use of the botanical kratom to self-manage opioid withdrawal and pain has led to increased kratom-linked overdose deaths. Despite these serious safety concerns, rigorous fundamental pharmacokinetic knowledge of kratom in humans remains lacking. We assessed the pharmacokinetics of a single low dose (2 g) of a well-characterized kratom product administered orally to six healthy participants. Median concentration-time profiles for the kratom alkaloids examined were best described by a two-compartment model with central elimination. Pronounced pharmacokinetic differences between alkaloids with the 3S configuration (mitragynine, speciogynine, paynantheine) and alkaloids with the 3R configuration (mitraciliatine, speciociliatine, isopaynantheine) were attributed to differences in apparent intercompartmental distribution clearance, volumes of distribution, and clearance. Based on noncompartmental analysis of individual concentration-time profiles, the 3S alkaloids exhibited a shorter median time to maximum concentration (1-2 vs. 2.5-4.5 h), lower area under the plasma concentration-time curve (430-490 vs. 794-5120 nM × h), longer terminal half-life (24-45 vs. ~12-18 h), and higher apparent volume of distribution during the terminal phase (960-12,700 vs. ~46-130 L) compared to the 3R alkaloids. Follow-up mechanistic in vitro studies suggested differential hepatic/intestinal metabolism, plasma protein binding, blood-to-plasma partitioning, and/or distribution coefficients may explain the pharmacokinetic differences between the two alkaloid types. This first comprehensive pharmacokinetic characterization of kratom alkaloids in humans provides the foundation for further research to establish safety and effectiveness of this emerging botanical product.

Refined Prediction of Pharmacokinetic Kratom-Drug Interactions: Time-Dependent Inhibition Considerations.

Preparations from the leaves of the kratom plant (Mitragyna speciosa) are consumed for their opioid-like effects. Several deaths have been associated with kratom used concomitantly with some drugs. Pharmacokinetic interactions are potential underlying mechanisms of these fatalities. Accumulating in vitro evidence has demonstrated select kratom alkaloids, including the abundant indole alkaloid mitragynine, as reversible inhibitors of several cytochromes P450 (CYPs). The objective of this work was to refine the mechanistic understanding of potential kratom-drug interactions by considering both reversible and time-dependent inhibition (TDI) of CYPs in the liver and intestine. Mitragynine was tested against CYP2C9 (diclofenac 4'-hydroxylation), CYP2D6 (dextromethorphan O-demethylation), and CYP3A (midazolam 1'-hydroxylation) activities in human liver microsomes (HLMs) and CYP3A activity in human intestinal microsomes (HIMs). Comparing the absence to presence of NADPH during preincubation of mitragynine with HLMs or HIMs, an ∼7-fold leftward shift in IC50 (∼20 to 3 µM) toward CYP3A resulted, prompting determination of TDI parameters (HLMs: K I , 4.1 ± 0.9 µM; k inact , 0.068 ± 0.01 min-1; HIMs: K I , 4.2 ± 2.5 µM; k inact , 0.079 ± 0.02 min-1). Mitragynine caused no leftward shift in IC50 toward CYP2C9 (∼40 µM) and CYP2D6 (∼1 µM) but was a strong competitive inhibitor of CYP2D6 (K i , 1.17 ± 0.07 µM). Using a recommended mechanistic static model, mitragynine (2-g kratom dose) was predicted to increase dextromethorphan and midazolam area under the plasma concentration-time curve by 1.06- and 5.69-fold, respectively. The predicted midazolam area under the plasma concentration-time curve ratio exceeded the recommended cutoff (1.25), which would have been missed if TDI was not considered. SIGNIFICANCE STATEMENT: Kratom, a botanical natural product increasingly consumed for its opioid-like effects, may precipitate potentially serious pharmacokinetic interactions with drugs. The abundant kratom indole alkaloid mitragynine was shown to be a time-dependent inhibitor of hepatic and intestinal cytochrome P450 3A activity. A mechanistic static model predicted mitragynine to increase systemic exposure to the probe drug substrate midazolam by 5.7-fold, necessitating further evaluation via dynamic models and clinical assessment to advance the understanding of consumer safety associated with kratom use.

Assessing Transporter-Mediated Natural Product-Drug Interactions Via In vitro-In Vivo Extrapolation: Clinical Evaluation With a Probe Cocktail.

The botanical natural product goldenseal can precipitate clinical drug interactions by inhibiting cytochrome P450 (CYP) 3A and CYP2D6. Besides P-glycoprotein, effects of goldenseal on other clinically relevant transporters remain unknown. Established transporter-expressing cell systems were used to determine the inhibitory effects of a goldenseal extract, standardized to the major alkaloid berberine, on transporter activity. Using recommended basic models, the extract was predicted to inhibit the efflux transporter BCRP and uptake transporters OATP1B1/3. Using a cocktail approach, effects of the goldenseal product on BCRP, OATP1B1/3, OATs, OCTs, MATEs, and CYP3A were next evaluated in 16 healthy volunteers. As expected, goldenseal increased the area under the plasma concentration-time curve (AUC0-inf ) of midazolam (CYP3A; positive control), with a geometric mean ratio (GMR) (90% confidence interval (CI)) of 1.43 (1.35-1.53). However, goldenseal had no effects on the pharmacokinetics of rosuvastatin (BCRP and OATP1B1/3) and furosemide (OAT1/3); decreased metformin (OCT1/2, MATE1/2-K) AUC0-inf (GMR, 0.77 (0.71-0.83)); and had no effect on metformin half-life and renal clearance. Results indicated that goldenseal altered intestinal permeability, transport, and/or other processes involved in metformin absorption, which may have unfavorable effects on glucose control. Inconsistencies between model predictions and pharmacokinetic outcomes prompt further refinement of current basic models to include differential transporter expression in relevant organs and intestinal degradation/metabolism of the precipitant(s). Such refinement should improve in vitro-in vivo prediction accuracy, contributing to a standard approach for studying transporter-mediated natural product-drug interactions.