Jee Sun Min

In vitro stereoselective inhibition of ginsenosides toward UDP-glucuronosyltransferase (UGT) isoforms.

We evaluated in vitro, the potential of the six pairs of ginsenoside isomers, stereoisomers at the chiral carbon on position 20, to inhibit the enzymatic activity of several UDP-glucuronosyltransferase (UGT) isoenzymes, major players in the human phase II drug metabolism. The results show that the tested six pairs of ginsenoside isomers exhibited stereoselective inhibitory effects of varying degrees on the ten UGT isoenzymes explored. Of the tested twelve stereoselective ginsenosides, 20(R)-Rg3 had the strongest inhibitory effect on the UGT1A8 isoform with the lowest IC50 value of 5.66±1.04μM. On the other hand, the (S)-isomers of Rg3 and Rh2 also exerted remarkable inhibition on UGT1A8, with IC50 values of 6.89±0.812μM and 5.85±0.821μM, respectively. Although the inhibitory effect was low, both 20(R)-PPT and 20(S)-PPT also inhibited UGT1A8 activity. Considering 1) that the relative contents of 20(R)-Rg3 in processed ginseng are high, 2) that higher exposure to (R)-isomers of ginsenosides occur in the intestine compared to that in the liver, and 3) the inhibitory effects of other ginsenosides on enzymatic activity [20(S)-Rg3, 20(S)-Rh2, 20(R)- and 20(S)-PPT], there may be a potential for herb-drug interactions between processed ginseng and UGT1A8 substrates when concomitantly administered.

In Vitro Inhibition of Human UDP-Glucuronosyl-Transferase (UGT) Isoforms by Astaxanthin, β-Cryptoxanthin, Canthaxanthin, Lutein, and Zeaxanthin: Prediction of in Vivo Dietary Supplement-Drug Interactions

Despite the widespread use of the five major xanthophylls astaxanthin, β-cryptoxanthin, canthaxanthin, lutein, and zeaxanthin as dietary supplements, there have been no studies regarding their inhibitory effects on hepatic UDP-glucuronosyltransferases (UGTs). Here, we evaluated the inhibitory potential of these xanthophylls on the seven major human hepatic UGTs (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15) in vitro by LC-MS/MS using specific marker reactions in human liver microsomes (except UGT2B15) or recombinant supersomes (UGT2B15). We also predicted potential dietary supplement-drug interactions for β-cryptoxanthin via UGT1A1 inhibition. We demonstrated that astaxanthin and zeaxanthin showed no apparent inhibition, while the remaining xanthophylls showed only weak inhibitory effects on the seven UGTs. β-Cryptoxanthin mildly inhibited UGT1A1, UGT1A3, and UGT1A4, with IC50 values of 18.8 ± 2.07, 28.3 ± 4.40 and 34.9 ± 5.98 μM, respectively. Canthaxanthin weakly inhibited UGT1A1 and UGT1A3, with IC50 values of 38.5 ± 4.65 and 41.2 ± 3.14 μM, respectively; and lutein inhibited UGT1A1 and UGT1A4, with IC50 values of 45.5 ± 4.01 and 28.7 ± 3.79 μM, respectively. Among the tested xanthophyll-UGT pairs, β-cryptoxanthin showed the strongest competitive inhibition of UGT1A1 (Ki, 12.2 ± 0.985 μM). In addition, we predicted the risk of UGT1A1 inhibition in vivo using the reported maximum plasma concentration after oral administration of β-cryptoxanthin in humans. Our data suggests that these xanthophylls are unlikely to cause dietary supplement-drug interactions mediated by inhibition of the hepatic UGTs. These findings provide useful information for the safe clinical use of the tested xanthophylls.

A simple and sensitive liquid chromatography–tandem mass spectrometry method for trans-ε-viniferin quantification in mouse plasma and its application to a pharmacokinetic study in mice

HIGHLIGHTSFirst LC–MS/MS method for trans‐&egr;‐viniferin quantification in mouse plasma.A simple protein precipitation that allowed for efficient/reproducible recovery yields was used.The small plasma volume (10 &mgr;l) supports the ability to examine pharmacokinetics in mice. ABSTRACT In this study, a simple and sensitive liquid chromatography‐tandem mass spectrometry (LC–MS/MS) method for the quantification of trans‐&egr;‐viniferin in small volumes (10 &mgr;l) of mouse plasma using chlorpropamide as an internal standard was developed and validated. Plasma samples were precipitated with acetonitrile and separated using an Eclipse Plus C18 column (100 × 4.6 mm, 1.8‐&mgr;m) with a mobile phase consisting of 0.1% formic acid in acetonitrile and 0.1% formic acid in water (60:40 v/v) at a flow rate of 0.5 ml/min. A triple quadrupole mass spectrometer operating in positive ion mode with selected reaction‐monitoring mode was used to determine trans‐&egr;‐viniferin and chlorpropamide transitions of 455.10 → 215.05 and 277.00 → 111.00, respectively. The lower limit of quantification was 5 ng/ml with a linear range of 5–2500 ng/ml (r ≥ 0.9949). All validation data, including the selectivity, precision, accuracy, recovery, dilution integrity, and stability, conformed to the acceptance requirements. No matrix effects were observed. The developed method was successfully applied to pharmacokinetic studies of trans‐&egr;‐viniferin following intravenous (2.5 mg/kg), intraperitoneal (2.5, 5 and 10 mg/kg), and oral (40 mg/kg) administration in mice. This is the first report on the pharmacokinetic properties of trans‐&egr;‐viniferin. The results provide a meaningful basis for evaluating the pre‐clinical or clinical applications of trans‐&egr;‐viniferin.

Polymer Micelle Formulation for the Proteasome Inhibitor Drug Carfilzomib: Anticancer Efficacy and Pharmacokinetic Studies in Mice

Carfilzomib (CFZ) is a peptide epoxyketone proteasome inhibitor approved for the treatment of multiple myeloma (MM). Despite the remarkable efficacy of CFZ against MM, the clinical trials in patients with solid cancers yielded rather disappointing results with minimal clinical benefits. Rapid degradation of CFZ in vivo and its poor penetration to tumor sites are considered to be major factors limiting its efficacy against solid cancers. We previously reported that polymer micelles (PMs) composed of biodegradable block copolymers poly(ethylene glycol) (PEG) and poly(caprolactone) (PCL) can improve the metabolic stability of CFZ in vitro. Here, we prepared the CFZ-loaded PM, PEG-PCL-deoxycholic acid (CFZ-PM) and assessed its in vivo anticancer efficacy and pharmacokinetic profiles. Despite in vitro metabolic protection of CFZ, CFZ-PM did not display in vivo anticancer efficacy in mice bearing human lung cancer xenograft (H460) superior to that of the clinically used cyclodextrin-based CFZ (CFZ-CD) formulation. The plasma pharmacokinetic profiles of CFZ-PM were also comparable to those of CFZ-CD and the residual tumors that persisted in xenograft mice receiving CFZ-PM displayed an incomplete proteasome inhibition. In summary, our results showed that despite its favorable in vitro performances, the current CFZ-PM formulation did not improve in vivo anticancer efficacy and accessibility of active CFZ to solid cancer tissues over CFZ-CD. Careful consideration of the current results and potential confounding factors may provide valuable insights into the future efforts to validate the potential of CFZ-based therapy for solid cancer and to develop effective CFZ delivery strategies that can be used to treat solid cancers.

Identification and characterization of in vitro inhibitors against UDP-glucuronosyltransferase 1A1 in uva-ursi extracts and evaluation of in vivo uva-ursi-drug interactions

Uva-ursi leaf is widely used to treat symptoms of lower urinary tract infections. Here, we evaluated the in vitro inhibitory effects of uva-ursi extracts on 10 major human UDP-glucuronosyltransferases (UGT) isoforms. Of the 10 tested UGT isoforms, uva-ursi extracts exerted the strongest inhibitory effect on UGT1A1-mediated β-estradiol 3-glucuronidation with the lowest IC50 value of 8.45 ± 1.56 μg/mL. To identify the components of uva-ursi extracts showing strong inhibitory effects against UGT1A1, the inhibitory effects of nine major constituents of the extracts were assessed. Among the tested compounds, gallotannin exerted the most potent inhibition on UGT1A1, followed by 1,2,3,6-tetragalloylglucose; both demonstrated competitive inhibition, with Ki values of 1.68 ± 0.150 μM and 3.55 ± 0.418 μM. We found that gallotannin and 1,2,3,6-tetragalloylglucose also inhibited another UGT1A1-specific biotransformation, SN-38-glucuronidation, showing the same order of inhibition. Thus, in vitro UGT1A1 inhibitory potentials of uva-ursi extracts might primarily result from the inhibitory activities of gallotannin and 1,2,3,6-tetragalloylglucose present in the extracts. However, in rats, co-administration with uva-ursi extracts did not alter the in vivo marker for UGT1A1 activity, expressed as the molar ratio of AUCSN-38 glucuronide/AUCSN-38, because plasma concentrations of gallotannin and 1,2,3,6-tetragalloylglucose may be too low to inhibit the UGT1A1-mediated metabolism of SN-38 in vivo. The poor oral absorption of gallotannin and 1,2,3,6-tetragalloylglucose in uva-ursi extracts might cause the poor in vitro-in vivo correlation. These findings will be helpful for the safe and effective use of uva-ursi extracts in clinical practice.

Quantitative determination of carfilzomib in mouse plasma by liquid chromatography–tandem mass spectrometry and its application to a pharmacokinetic study

HIGHLIGHTSA rapid and simple LC–MS/MS assay for carfilzomib was validated.Sample preparation involved a simple deproteinization with acetonitrile.The total chromatographic run time was 2.5 min.The LLOQ was 0.075 ng/mL in 5 mL of plasma.The assay may allow serial blood sampling from one mouse in pharmacokinetic studies. ABSTRACT A highly sensitive and rapid LC–MS/MS method was developed and validated to determine the levels of carfilzomib in mice plasma by using chlorpropamide as an internal standard. Carfilzomib and chlorpropamide were extracted from 5 &mgr;L of plasma after protein precipitation with acetonitrile. Chromatographic separation was performed on Phenomenex Luna C18 column (50 × 2.0 mm id, 3 &mgr;m). The mobile phase consisted of 0.1% formic acid in acetonitrile −0.1% formic acid in water (1:1 v/v) and the flow rate was 0.3 mL/min. The total chromatographic run time was 2.5 min. Detection was performed on a triple quadrupole mass spectrometer equipped with positive‐ion electrospray ionization by selected reaction monitoring of the transitions at m/z 720.20 > 100.15 (for carfilzomib) and m/z 277.05 > 111.05 (for the internal standard). The lower limit of quantification was 0.075 ng/mL and the linear range was 0.075–1250 ng/mL (r ≥ 0.9974). All validation data, including selectivity, precision, accuracy, matrix effect, recovery, dilution integrity, stability, and incurred sample reanalysis, were well within acceptance limits. This newly developed bioanalytical method was simple, highly sensitive, required only a small volume of plasma, and was suitable for application in pharmacokinetic studies in mice that used serial blood sampling.

Prediction of drug–drug interaction potential using physiologically based pharmacokinetic modeling

The occurrence of drug–drug interactions (DDIs) can significantly affect the safety of a patient, and thus assessing DDI risk is important. Recently, physiologically based pharmacokinetic (PBPK) modeling has been increasingly used to predict DDI potential. Here, we present a PBPK modeling concept and strategy. We also surveyed PBPK-related articles about the prediction of DDI potential in humans published up to October 10, 2017. We identified 107 articles, including 105 drugs that fit our criteria, with a gradual increase in the number of articles per year. Studies on antineoplastic and immunomodulatory drugs (26.7%) contributed the most to published PBPK models, followed by cardiovascular (20.0%) and anti-infective (17.1%) drugs. Models for specific products such as herbal products, therapeutic protein drugs, and antibody–drug conjugates were also described. Most PBPK models were used to simulate cytochrome P450 (CYP)-mediated DDIs (74 drugs, of which 85.1% were CYP3A4-mediated), whereas some focused on transporter-mediated DDIs (15 drugs) or a combination of CYP and transporter-mediated DDIs (16 drugs). Full PBPK, first-order absorption modules and Simcyp® software were predominantly used for modeling. Recently, DDI predictions associated with genetic polymorphisms, special populations, or both have increased. The 107 published articles reasonably predicted the DDI potentials, but further studies of physiological properties and harmonization of in vitro experimental designs are required to extend the application scope, and improvement of DDI predictions using PBPK modeling will be possible in the future.

Application of Physiologically Based Pharmacokinetic Modeling In Predicting Drug-Drug Interactions For Sarpogrelate Hydrochloride In Humans.

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Pharmacokinetic properties of trifolirhizin, (–)-maackiain, (–)-sophoranone and 2-(2,4-dihydroxyphenyl)-5,6-methylenedioxybenzofuran after intravenous and oral administration of Sophora tonkinensis extract in rats

Abstract 1. SKI3301, a standardized dried 50% ethanolic extracts of Sophora tonkinensis, contains four marker compounds (trifolirhizin, TF; (–)-maackiain, Maack; (–)-sophoranone, SPN, and (2-(2,4-dihydroxyphenyl)-5,6-methylenedioxybenzofuran, ABF), is being developed as an herbal medicine for the treatment of asthma in Korea. This study investigates the pharmacokinetic properties of SKI3301 extract in rats. 2. The dose-proportional AUCs suggest linear pharmacokinetics of TF, Maack, SPN and ABF in the SKI3301 extract intravenous dose range of 5–20 mg/kg. After the oral administration of 200–1000 mg/kg of the extract, TF and Maack exhibited non-linearity due to the saturation of gastrointestinal absorption. However, linear pharmacokinetics of SPN and ABF were observed. 3. The absorptions of TF, Maack, SPN and ABF in the extract were increased relative to those of the respective pure forms due to the increased solubility and/or the decreased metabolism by other components in the SKI3301 extract. 4. No accumulation was observed after multiple dosing, and the steady-state pharmacokinetics of TF, Maack, SPN and ABF were not significantly different from those after a single oral administration of the extract. 5. The pharmacokinetics of TF, SPN and ABF were not significantly different between male and female rats after oral administration of the extract, but a significant gender difference in the pharmacokinetics of Maack in rats was observed. 6. Our findings may help to comprehensively elucidate the pharmacokinetic characteristics of TF, Maack, SPN and ABF and provide useful information for the clinical application of SKI3301 extract.