15^th Euro-Global Summit on Toxicology and Applied Pharmacology July 02-04, 2018 Golden Tulip Berlin – Hotel Hamburg | Berlin, Germany

Soo Hyun Jang is a graduate student with major in Pharmacology/Pharmacokinetics from The Catholic University of Korea, Republic of South Korea. His research interest include: in vitro herb-drug interaction, nonclinical pharmacokinetics and bioanalysis development.

Sophora tonkinensis is a traditional medicine used for the treatment of asthma, allergic dermatitis, and throat inflammation in China and Korea. The present study was performed to evaluate the in vitro inhibitory potential of sophoranone, one of marker components of Sophora tonkinensis, on the \r\nactivities of nine human cytochrome (CYP) isoforms. Using an LC-MS/MS cocktail assay, the effects of sophoranone on specific marker reactions of the nine CYP isoforms were measured in human liver microsomes. Sophoranone showed potent inhibition of CYP2C9-mediated tolbutamide 4-hydroxylation with an IC50 value of 1.21 µM and Ki value of 0.418 µM in a competitive manner; this was similarly potent as a well-known typical CYP2C9 inhibitor, sulfaphenazole (Ki=0.398 µM). In addition, sophoranone slightly inhibited CYP2C8 and CYP2C19 activities (IC50 values of 17.8 µM and 16.4 µM). These observations indicated 13.6- and 12.5-fold decreases in inhibition potency, respectively, compared with that of CYP2C9 by sophoranone. However, no inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1, or CYP3A activities was observed. These observations suggest that sophoranone is a selective and potent inhibitor of CYP2C9 in vitro, whereas inhibition of other CYPs is substantially lower. These in vitro data support that Sophora tonkinensis extract or sophoranone as a single compound may cause herb-drug interactions via inhibition of CYP2C9, and precautions should be taken when Sophora tonkinensis extract or sophoranone is co-administered with drugs that are mainly metabolized by CYP2C9. \r\n

Soon Uk Chae is a graduate student with major in Pharmacology/Pharmacokinetics from The Catholic University of Korea. His research interests include: in vitro herb-drug interaction, nonclinical pharmacokinetics and bioanalysis development.

BST204 is a purified ginseng dry extract that is a highly concentrated mixture of racemic (1:1) Rh2 (not less than 5.0%) and Rg3 (not less than 10.0%) developed by Green Cross Health Science (Republic of South Korea). It is undergoing Phase IIa clinical trials for the treatment of cancer cachexia in Europe. We previously reported that oral dosing of BST204 extract had no effect on the pharmacokinetics of two anti-cancer drugs, 5-fluorouracil, and irinotecan, after intravenous dosing in rats. This study aimed to investigate the influences of BST204 extract on the oral absorption and disposition of imatinib, an oral cancer drug, in rats. Rats were orally administered imatinib (30 mg/kg) alone and in combination with BST204 extract (1 g/kg or 0.2 g/kg) concomitantly, respectively. Plasma concentrations of imatinib and N-desmethyl imatinib were determined using an LC-MS/MS. Pharmacokinetic parameters were calculated using a non-compartment model of WinNonlin software. High oral dose of BST204 extract (1 g/kg) resulted in marked reductions (62.1% decrease) in the maximum concentration (Cmax) and increases (6-fold) in the time to reach a Cmax (Tmax), respectively, as compared with imatinib alone, while the terminal half-life of imatinib was not different between two groups. Similar patterns of N-desmethyl imatinib, which are decreased Cmax and delayed Tmax, were observed by co-administration with high oral dose of BST204 extract. In contrast, the pharmacokinetics of imatinib and N-desmethyl imatinib were not altered by orally in combination with low dose of BST204 (0.2 g/kg). In conclusion, high dose of BST204 extract significantly decreased the oral bioavailability of imatinib, and the interaction should occur at the absorption phase, possibly through the inhibition of its intestinal absorption mediated by uptake transporters. We suggest that concurrent intake of BST204 extract with imatinib are better avoided in order to ensure the efficacy of imatinib.

Chae Bin Lee is a graduate student with major in Pharmacology/Pharmacokinetics from The Catholic University of Korea. Her research interest include: in vitro herb-drug interaction, nonclinical pharmacokinetics and bio analysis development.

Organic anion transporting polypeptide (OATP) 1B3 plays an essential role in the hepatic uptake of many drugs and the assessment of OATP1B3-mediated drug-drug interactions is recently emphasized. The main active components of ginseng are ginsenosides, a diverse group of triterpenoid saponins that exert a variety of pharmacological activities including anti-inflammatory, anti-cancer, anti-diabetic, and cardioprotective effects. Of these, ginsenoside Rh2 is mainly recognized as an anti-cancer compound, and contains the two epimeric forms, 20(R)-Rh2 and 20(S)-Rh2. It was reported that the stereochemistry of the C-20 hydroxyl group [i.e. 20(R)-Rh2 and 20(S)-Rh2] not only plays a role in the pharmacodynamics of ginsenosides but also in their pharmacokinetic properties. The aim of this study was to evaluate the human organic anion transporting polypeptide 1B3 (OATP1B3)-mediated drug-drug interaction potential of ginsenoside Rh2 (Rh2) epimers, 20(R)-Rh2 and 20(S)-Rh2, using human embryonic kidney 293 (HEK293) cells overexpressing OATP1B3 (HEK293-OATP1B3). The inhibition of estradiol 17β-D-glucuronide transport by ginsenoside Rh2 epimers were assessed in HEK293-OATP1B1. Our results showed that both 20(R)-Rh2 and 20(S)-Rh2 exhibited different potencies of stereoselective inhibition on the OATP1B3 uptake. 20(S)-Rh2 exerted marked inhibition with and IC50 value of 17.1±7.10 μM, whereas their (R)-isomer did not inhibit OATP1B3 uptake activity.