Assessment of Metabolic Interaction between Repaglinide and Quercetin via Mixed Inhibition in the Liver: In Vitro and In Vivo

Repaglinide (RPG), a rapid-acting meglitinide analog, is an oral hypoglycemic agent for patients with type 2 diabetes mellitus. Quercetin (QCT) is a well-known antioxidant and antidiabetic flavonoid that has been used as an important ingredient in many functional foods and complementary medicines. This study aimed to comprehensively investigate the effects of QCT on the metabolism of RPG and its underlying mechanisms. The mean (range) IC50 of QCT on the microsomal metabolism of RPG was estimated to be 16.7 (13.0–18.6) μM in the rat liver microsome (RLM) and 3.0 (1.53–5.44) μM in the human liver microsome (HLM). The type of inhibition exhibited by QCT on RPG metabolism was determined to be a mixed inhibition with a Ki of 72.0 μM in RLM and 24.2 μM in HLM as obtained through relevant graphical and enzyme inhibition model-based analyses. Furthermore, the area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax) of RPG administered intravenously and orally in rats were significantly increased by 1.83- and 1.88-fold, respectively, after concurrent administration with QCT. As the protein binding and blood distribution of RPG were observed to be unaltered by QCT, it is plausible that the hepatic first-pass and systemic metabolism of RPG could have been inhibited by QCT, resulting in the increased systemic exposure (AUC and Cmax) of RPG. These results suggest that there is a possibility that clinically significant pharmacokinetic interactions between QCT and RPG could occur, depending on the extent and duration of QCT intake from foods and dietary supplements.

In Vitro Interaction of AB-FUBINACA with Human Cytochrome P450, UDP-Glucuronosyltransferase Enzymes and Drug Transporters

AB-FUBINACA, a synthetic indazole carboxamide cannabinoid, has been used worldwide as a new psychoactive substance. Because drug abusers take various drugs concomitantly, it is necessary to explore potential AB-FUBINACA-induced drug–drug interactions caused by modulation of drug-metabolizing enzymes and transporters. In this study, the inhibitory effects of AB-FUBINACA on eight major human cytochrome P450s (CYPs) and six uridine 5′-diphospho-glucuronosyltransferases (UGTs) of human liver microsomes, and on eight clinically important transport activities including organic cation transporters (OCT)1 and OCT2, organic anion transporters (OAT)1 and OAT3, organic anion transporting polypeptide transporters (OATP)1B1 and OATP1B3, P-glycoprotein, and breast cancer resistance protein (BCRP) in transporter-overexpressing cells were investigated. AB-FUBINACA inhibited CYP2B6-mediated bupropion hydroxylation via mixed inhibition with Ki value of 15.0 µM and competitively inhibited CYP2C8-catalyzed amodiaquine N-de-ethylation, CYP2C9-catalyzed diclofenac 4′-hydroxylation, CYP2C19-catalyzed [S]-mephenytoin 4′-hydroxylation, and CYP2D6-catalyzed bufuralol 1′-hydroxylation with Ki values of 19.9, 13.1, 6.3, and 20.8 µM, respectively. AB-FUBINACA inhibited OCT2-mediated MPP+ uptake via mixed inhibition (Ki, 54.2 µM) and competitively inhibited OATP1B1-mediated estrone-3-sulfate uptake (Ki, 94.4 µM). However, AB-FUBINACA did not significantly inhibit CYP1A2, CYP2A6, CYP3A4, UGT1A1, UGT1A3, UGT1A4, UGT1A6, or UGT2B7 enzyme activities at concentrations up to 100 µM. AB-FUBINACA did not significantly inhibit the transport activities of OCT1, OAT1/3, OATP1B3, P-glycoprotein, or BCRP at concentrations up to 250 μM. As the pharmacokinetics of AB-FUBINACA in humans and animals remain unknown, it is necessary to clinically evaluate potential in vivo pharmacokinetic drug–drug interactions induced by AB-FUBINACA-mediated inhibition of CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, OCT2, and OATP1B1 activities.

SINTESIS, KARAKTERISASI DAN UJI AKTIVITAS SENYAWA KOMPLEKS Zn(II)-KATEKIN SEBAGAI INHIBITOR ENZIM LIPASE

ABSTRACT The study aims to synthesis, characterization and activity testing of Zn(II)-catechin as lipase inhibitor activity. The complex compound from synthesis result is characterized by its maximum wavelength, functional groups, metals and ligands bonds, and it’s melting point. This complex compound tested of Zn(II)-catechin as lipase inhibitor activity to p-NPP (para-nitrofenilpalmitat) substrate. The result shows that Zn(II)-catechin could be synthesized from Zn(II) ligans and metals with ratio ligands and metals mol is 1:1, that has maximum wavelength 454 nm, which contain Zn-O bond at 354,90 and 478,35 cm-1, and melting point of Zn(II)-catechin >250 oC. Zn(II)-catechin can inhibition 60,63% from concentration 50 µg/mL with mixed inhibition Keyword : Zn(II)-catechin, lipase, mixed inhibition ABSTRAK Penelitian ini bertujuan untuk melakukan sintesis, karakterisasi dan uji aktivitas senyawa kompleks Zn(II)-katekin terhadap aktivitas inhibitor enzim lipase. Senyawa kompleks hasil sintesis dikarakterisasi panjang gelombang maksimumnya, gugus fungsi serta ikatan logam dan ligannya, serta titik lelehnya. Senyawa kompleks diuji aktivitas inhibitor enzim lipase terhadap substrat p-NPP (paranitrofenilpalmitat). Hasil penelitian menunjukkan bahwa senyawa kompleks Zn(II)-katekin dapat disintesis dari ligan katekin dan logam Zn(II) dengan perbandingan mol ligan logam 1:1, mempunyai panjang gelombang maksimum 454 nm, mengandung ikatan Zn-O pada 354,90 dan 478,35 cm-1 dan titik leleh senyawa kompleks >250 oC. Senyawa kompleks Zn(II)-katekin pada konsentrasi 50µg/mL mempunyai daya inhinbisi sebesar 60,63% terhadap enzim lipase dengan jenis inhibisi campuran. Kata kunci : Zn(II)-katekin, lipase, inhibitor campuran

Inhibition of α-Amylases by Condensed and Hydrolysable Tannins: Focus on Kinetics and Hypoglycemic Actions

The aim of the present study was to compare the in vitro inhibitory effects on the salivary and pancreatic α-amylases and the in vivo hypoglycemic actions of the hydrolysable tannin from Chinese natural gall and the condensed tannin from Acacia mearnsii. The human salivary α-amylase was more strongly inhibited by the hydrolysable than by the condensed tannin, with the concentrations for 50% inhibition (IC50) being 47.0 and 285.4 μM, respectively. The inhibitory capacities of both tannins on the pancreatic α-amylase were also different, with IC50 values being 141.1 μM for the hydrolysable tannin and 248.1 μM for the condensed tannin. The kinetics of the inhibition presented complex patterns in that for both inhibitors more than one molecule can bind simultaneously to either the free enzyme of the substrate-complexed enzyme (parabolic mixed inhibition). Both tannins were able to inhibit the intestinal starch absorption. Inhibition by the hydrolysable tannin was concentration-dependent, with 53% inhibition at the dose of 58.8 μmol/kg and 88% inhibition at the dose of 294 μmol/kg. For the condensed tannin, inhibition was not substantially different for doses between 124.4 μmol/kg (49%) and 620 μmol/kg (57%). It can be concluded that both tannins, but especially the hydrolysable one, could be useful in controlling the postprandial glycemic levels in diabetes.

Eco-Friendly Corrosion Inhibition of Pipeline Steel UsingBrassica oleracea

The inhibition capacity ofBrassica oleracea(BO) extract on the corrosion of pipeline steel in 0.5 M H2SO4was evaluated using electrochemical techniques. The results showed an excellent inhibition efficiency which increased with initial increase in extract concentration and temperature to a point and decreased with further increase in BO extract concentration and temperature. Mixed inhibition behaviour was proposed for the action of BO. The unique behaviour of BO was attributed to the organic entities present in the extract.