Identification of glucuronidation and biliary excretion as the main mechanisms for gossypol clearance:in vivoandin vitroevidence

Abstract

1. The natural polyphenol gossypol possesses many therapeutic benefits. Here we aim to determine the elimination pathways of gossypol in vivo and in vitro. 2. Metabolite elucidation of gossypol was performed using UPLC-QTOF/MS coupled with Metabolynx analysis. Clearance of gossypol was evaluated in bile duct cannulated rats and in the single-pass perfused rat intestine model. In vitro glucuronidation of gossypol was characterized using liver and intestine microsomes as well as recombinant UDP-glucuronosyltransferase (UGT) enzymes. 3. Analysis of rat plasma, urine, and feces revealed glucuronidation as the only metabolic pathway for gossypol. In bile duct cannulated rats, considerable amounts of glucuronides (G1, G2 and G3; 58.8-83.2% of dose) and parent compound (5.0-20%) were excreted into bile after IV administration. In the perfused rat intestine model, gossypol was well absorbed with a [Formula: see text] (the dimensionless effective permeability) value of 4.4. Significant amounts of glucuronides (G1, G2 and G3) were excreted into the gut lumen (2.5%) and into the bile (4.8%). Biliary excretion of unchanged gossypol (6.0%) was comparable to that of glucuronides. Further, gossypol was subjected to rapid glucuronidation by liver and intestine microsomes. Reaction phenotyping showed that multiple UGT1A enzymes (including UGT1A1, 1A3, 1A7 and 1A8) are mainly responsible for gossypol metabolism. 4. In conclusion, glucuronidation was the only metabolic pathway for gossypol in rats. Excretion of unchanged gossypol into bile was also an important clearance mechanism.

Nanosuspensions Containing Oridonin/HP-β-Cyclodextrin Inclusion Complexes for Oral Bioavailability Enhancement via Improved Dissolution and Permeability

“…Quantitation was processed based on the full scan analysis and extracted ion chromatograms using MassLynx version 4.1. The configuration and parameter settings of instrument were consistent with the published literature (14).…”

Mixed nanomicelles as potential carriers for systemic delivery of Z-GP-Dox, an FAPα-based doxorubicin prodrug: formulation and pharmacokinetic evaluation

“…Quantitation was performed based on the full scan analysis and extracted ion chromatograms using MassLynx version 4.1 as described elsewhere. 25,26 A typical chromatogram for analysis of Z-GPDox is shown with the drug molecule eluted at 2.73 minutes in Figure 1B.…”

“…25 The concentrations of Z-GP-Dox in these samples were analyzed by UPLC-QTOF/MS. The heart, liver, spleen, lung, kidney, and intestinal tissues were homogenized in saline solution (1:2, w/v).…”

Elucidating the in vivo fate of nanocrystals using a physiologically based pharmacokinetic model: a case study with the anticancer agent SNX-2112

“…All other tissues were lumped into a remainder (rm) compartment ( Figure 1A). Elimination of SNX-2112 primarily occurred in the liver, 41 which was represented by the apparent hepatic clearance CL h . Drug concentrations in each tissue were determined by the tissue/plasma partition coefficient (K p,ti ), plasma flow (Q ti ), and organ volume (V ti ).…”

“…41 The concentrations of SNX-2112 in the samples were analyzed by the ultra-performance liquid chromatography quadrupole time-of flight mass spectrometry (UPLC-QTOF/MS) system. The heart, liver, spleen, lung, kidney, and intestine tissues were homogenized 1:2 (w/v) in saline solution.…”