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

James T. Nguyen, Dan Dan Tian, Rakshit S. Tanna, Deena L. Hadi, Sumit Bansal, Justina C. Calamia, Christopher M. Arian, Laura M. Shireman, Bálint Molnár, Miklós Horváth, Joshua J. Kellogg, Matthew E. Layton, John R. White, Nadja B. Cech, Richard D. Boyce, Jashvant D. Unadkat, Kenneth E. Thummel, Mary F. Paine

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
JournalClinical pharmacology and therapeutics
DOIs
StateAccepted/In press - 2020

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

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