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

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.

Crystal Structure, Solubility, and Pharmacokinetic Study on a Hesperetin Cocrystal with Piperine as Coformer

“…Currently, many other water-soluble components were selected for drugs' cocrystals, such as nicotinamide, isonicotinamide, theobromine, theophylline, caffeine, betaine, and urea [25][26][27][28][29]. Although solubility is a major limiting factor in hydrophobic drugs' bioavailability, the efflux of intestinal P-glycoprotein (P-gp), the metabolism of cytochrome P450, and the degradation of drugs by intestinal bacterial enzymes also significantly contribute to reduce drugs' oral bioavailability [30,31]. Therefore, an integrated strategy that uses a suitable bioenhancer along with poorly soluble drugs to form cocrystals not only can maintain the desired supersaturation but also reduce the efflux of drugs to improve bioavailability.…”

“…This enhancement in solubility of cocrystal UA-PIP arose from the hydrogen bond between the two molecules, which destroyed the long-range order of the component, and improvement of solubility helped achieve sufficient concentration in blood. Importantly, the inhibitory effect on P-gp and CYP3A4 induced by PIP, to some extent, was responsible for the prolonged systemic exposure of drugs, thereby in- Although solubility is a major limiting factor in hydrophobic drugs' bioavailability, the efflux of intestinal P-glycoprotein (P-gp), the metabolism of cytochrome P450, and the degradation of drugs by intestinal bacterial enzymes also significantly contribute to reduce drugs' oral bioavailability [30,31]. Therefore, an integrated strategy that uses a suitable bioenhancer along with poorly soluble drugs to form cocrystals not only can maintain the desired supersaturation but also reduce the efflux of drugs to improve bioavailability.…”

Transporter-mediated Natural Product-Drug Interactions

“…Although the goldenseal extract shows a strong inhibitory effect on OCT1, OCT2, MATE1, and MATE2-K in HEK293 transporter-overexpressing cells, it significantly decreases the AUC of metformin in healthy subjects without affecting its half-life and renal clearance [42]. The discrepancy between the in vitro and in vivo findings could be attributable to the effect of the goldenseal extract on the intestinal absorption of metformin.…”

Adapting regulatory drug‐drug interaction guidance to design clinical pharmacokinetic natural product‐drug interaction studies: A NaPDI Center recommended approach

“…18 Regarding transporter-mediated NPDIs, basic models were used to predict whether an interaction would occur between goldenseal and the transporter probe drugs furosemide, metformin, and rosuvastatin. 19 Additional examples are summarized in the NaPDI Center's most recent Recommended Approach. 15 If biophysical and in vitro NPDI data are available and suggest an NPDI, a phase 0 study is merited to describe pharmacokinetic behavior of select phytoconstituents (targeted based on abundance and plausibility of biological effects) and recover fundamental metrics (e.g., area under the blood or plasma concentration versus time curve [AUC], maximum concentration [C max ], time to reach C max [t max ], terminal half-life ]t 1/2 ], and renal clearance if urine is collected).…”

“… 18 Regarding transporter‐mediated NPDIs, basic models were used to predict whether an interaction would occur between goldenseal and the transporter probe drugs furosemide, metformin, and rosuvastatin. 19 Additional examples are summarized in the NaPDI Center’s most recent Recommended Approach. 15 …”