Inhibitory Effect of Sauchinone on UDP-Glucuronosyltransferase (UGT) 2B7 Activity

Herb–drug interaction (HDI) limits clinical application of herbs and drugs, and inhibition of herbs towards uridine diphosphate (UDP)-glucuronosyltransferases (UGTs) has gained attention as one of the important reasons to cause HDIs. Sauchinone, an active lignan isolated from aerial parts of Saururus chinensis (Saururacease), possesses anti-oxidant, anti-inflammatory, and anti-viral activities. In pharmacokinetics of sauchinone, sauchinone is highly distributed to the liver, forming extensive metabolites of sauchinone via UGTs in the liver. Thus, we investigated whether sauchinone inhibited UGTs to explore potential of sauchinone–drug interactions. In human liver microsomes (HLMs), sauchinone inhibited activities of UGT1A1, 1A3, 1A6, and 2B7 with IC50 values of 8.83, 43.9, 0.758, and 0.279 μM, respectively. Sauchinone also noncompetitively inhibited UGT1A6 and 2B7 with Ki values of 1.08 and 0.524 μM, respectively. In in vivo interaction study using mice, sauchinone inhibited UGT2B7-mediated zidovudine metabolism, resulting in increased systemic exposure of zidovudine when sauchinone and zidovudine were co-administered together. Our results indicated that there is potential HDI between sauchinone and drugs undergoing UGT2B7-mediated metabolism, possibly contributing to the safe use of sauchinone and drug combinations

Quantum Artificial Neural Network Approach to Derive a Highly Predictive 3D-QSAR Model for Blood–Brain Barrier Passage

A successful passage of the blood–brain barrier (BBB) is an essential prerequisite for the drug molecules designed to act on the central nervous system. The logarithm of blood–brain partitioning (LogBB) has served as an effective index of molecular BBB permeability. Using the three-dimensional (3D) distribution of the molecular electrostatic potential (ESP) as the numerical descriptor, a quantitative structure-activity relationship (QSAR) model termed AlphaQ was derived to predict the molecular LogBB values. To obtain the optimal atomic coordinates of the molecules under investigation, the pairwise 3D structural alignments were conducted in such a way to maximize the quantum mechanical cross correlation between the template and a target molecule. This alignment method has the advantage over the conventional atom-by-atom matching protocol in that the structurally diverse molecules can be analyzed as rigorously as the chemical derivatives with the same scaffold. The inaccuracy problem in the 3D structural alignment was alleviated in a large part by categorizing the molecules into the eight subsets according to the molecular weight. By applying the artificial neural network algorithm to associate the fully quantum mechanical ESP descriptors with the extensive experimental LogBB data, a highly predictive 3D-QSAR model was derived for each molecular subset with a squared correlation coefficient larger than 0.8. Due to the simplicity in model building and the high predictability, AlphaQ is anticipated to serve as an effective computational screening tool for molecular BBB permeability

Evaluation of Pharmacokinetic Feasibility of Febuxostat/L-pyroglutamic Acid Cocrystals in Rats and Mice

Febuxostat (FBX), a selective xanthine oxidase inhibitor, belongs to BCS class II, showing low solubility and high permeability with a moderate F value (F) values of FBX were 210% and 159% in FBX-PG-treated rats and mice, respectively. The 2.10-fold greater total area under the plasma concentration–time curve from time zero to infinity (AUC0-inf) of FBX was due to the increased absorption [i.e., 2.60-fold higher the first peak plasma concentration (Cmax,1) at 15 min] and entero-hepatic circulation of FBX [i.e., 1.68-fold higher the second peak plasma concentration (Cmax,2) at 600 min] in FBX-PG-treated rats compared to the FBX-treated rats. The 1.59-fold greater AUC0-inf of FBX was due to a 1.65-fold higher Cmax,1 at 5 min, and a 1.15-fold higher Cmax,2 at 720 min of FBX in FBX-PG-treated mice compared to those in FBX-treated mice. FBX was highly distributed in the liver, stomach, small intestine, and lungs in both groups of mice, and the FBX distributions to the liver and lungs were increased in FBX-PG-treated mice compared to FBX-treated mice. The results suggest the FBX-PG has a suitable pharmacokinetic profile of FBX for improving its oral F value

Spectrums of α-MG and its tentative metabolites (M1–M5) detected in mice’s plasma, urine, feces, liver and small intestine after intravenous and oral administration of α-MG and S9 fractions of the liver and small intestine after 30 min incubation.

<p>Spectrums of α-MG and its tentative metabolites (M1–M5) detected in mice’s plasma, urine, feces, liver and small intestine after intravenous and oral administration of α-MG and S9 fractions of the liver and small intestine after 30 min incubation.</p

Dose-Independent ADME Properties and Tentative Identification of Metabolites of α-Mangostin from <i>Garcinia mangostana - Fig 1 </i> in Mice by Automated Microsampling and UPLC-MS/MS Methods

<p>Mean plasma concentration of α-MG after intravenous administration of α-MG at doses of 5 (●), 10 (○) and 20 (□) mg/kg to mice (A). Also plasma concentration of α-MG after oral administration of α-MG at doses of 10 (●), 50 (○) and 100 (□) mg/kg to mice (B). Bars represent SDs.</p

Mean (± SD) plasma concentration of α-MG after intravenous and oral administration of α-MG to mice.

<p>All values were statistically analyzed and all of them were not statistically different (p < 0.05) except AUC and C_max values among three doses.</p><p>^<b>a</b> Statistically different (p < 0.05) among three doses.</p><p>^b Normalized values based on 1 mg/kg were not statistically different among three doses.</p><p>^c Median (ranges) for <i>T</i>_max.</p><p>Mean (± SD) plasma concentration of α-MG after intravenous and oral administration of α-MG to mice.</p

Proposed structures and metabolic pathways of metabolites in mice’s plasma, urine, feces, liver and small intestine after intravenous and oral administration of α-MG and S9 fractions of the liver and small intestine after 30 min incubation.

<p>Proposed structures and metabolic pathways of metabolites in mice’s plasma, urine, feces, liver and small intestine after intravenous and oral administration of α-MG and S9 fractions of the liver and small intestine after 30 min incubation.</p

Mean T/P ratios of α-MG from various tissues at 30 (■) and 180 (□) min after intravenous (A) and oral (B) administration of α-MG at a dose of 10 mg/kg to mice.

<p>Bars represent SDs.</p

Mean values for the disappearance of α-MG after spiking 1 (■) or 20 (□) μg/mL of α-MG into S9 fractions of various tissues from mice.

<p>Bars represent SDs.</p