Theoretical Study on Reactions of Triplet Excited State Thioxanthone with Indole

In the present work, a theoretical study on the deactivation of triplet excited (T1) state thioxanthone (TX) by indole (INH) was performed, based on density functional theory calculations. Three feasible pathways, namely direct electron transfer from INH to T1 state TX, electron transfer followed by proton transfer from INH.+ to TX.−, and H-atom transfer from nitrogen of INH to keto oxygen of T1 state TX, were proposed theoretically to be involved in T1 state TX deactivation by INH

In vitro permeability studies of antitumor compounds, thioxanthones across two model barriers, and their availability in vivo

One of the reasons for poor response of tumors is their three dimensional structure (micro-environment), which forms a penetration barrier to anti-tumor agents. A drug has to cross the interstitial space of tumors and many layers of cells to reach the interior of a tumor. The main objective of this study was to develop two new in vitro models to evaluate the in vivo availability of antitumor compounds to solid tumors. Two in vitro models, basement membrane p:1atrix of Engelbreth-Holm Swarm (EHS) mouse sarcoma (Matrigel) and human colorectal adenocarcinoma (Caco-2) multilayers were developed. The permeability characteristics of SR271425 (N-[1-{ [2-(diethylamino) ethyl] amino} -7 -methoxy-9-oxo-9H -thioxanthen-4-yl] methylformamide) a novel antitumor compound and three of its thioxanthone analogs (probable metabolites) were studied to evaluate the in vitro models

In vitro permeability studies of antitumor compounds, thioxanthones across two model barriers, and their availability in vivo

One of the reasons for poor response of tumors is their three dimensional structure (micro-environment), which forms a penetration barrier to anti-tumor agents. A drug has to cross the interstitial space of tumors and many layers of cells to reach the interior of a tumor. The main objective of this study was to develop two new in vitro models to evaluate the in vivo availability of antitumor compounds to solid tumors. Two in vitro models, basement membrane p:1atrix of Engelbreth-Holm Swarm (EHS) mouse sarcoma (Matrigel) and human colorectal adenocarcinoma (Caco-2) multilayers were developed. The permeability characteristics of SR271425 (N-[1-{ [2-(diethylamino) ethyl] amino} -7 -methoxy-9-oxo-9H -thioxanthen-4-yl] methylformamide) a novel antitumor compound and three of its thioxanthone analogs (probable metabolites) were studied to evaluate the in vitro models

Factors contributing to and predictive models for drugs exhibiting negative food effects of unknown mechanisms

Drugs exhibiting decreased extent of absorption in the fed state administration when compared to the fasted state administration are termed to exhibit a negative food effect. The known causes for negative food effects are luminal degradation and complexation to metal ions/Ca 2+ . For the drugs that do not undergo GI degradation and metal ion complexation, different factors were attributed to cause negative food effects, which are inconclusive. The objectives of this investigation were; to identify the physicochemical and physiological changes between fasted and fed states and their role in causing negative food effects; to develop an empirical model that correlates the biopharmaceutical properties of molecules to negative food effects; and translate the empirical model to a mechanistic model and explain the mechanisms of negative food effects for drugs that do not have clearly defined mechanisms of negative food effects. The important physicochemical change in the upper intestine was identified to be pH. The pH of the upper intestine in the fasted state is typically 6.5, whereas, the overall post-prandial pH after a standard meal in the duodenum is 5.4 (5.0 − 5.7) and the jejunal pH is 4.7 owing to the emptying of acidic chyme. Negative food effect drugs exhibited incomplete GI absorption, low Log P values and low apical to basolateral Caco-2 permeabilities. Acidic/basic drugs exhibiting either negative food effects or no food effects with a molecular size range of 200–450 Da and no physiological effects (such as secretions and motility) were selected from the literature. Multiple linear regression analysis using five drugs exhibiting negative food effects and seven drugs exhibiting no food effects indicated that, percent food effects correlated to acidic/basic dissociation constants (Ka/Kb) and to Caco-2 permeability (R 2 = 0.9114, Power ≈ 1 and p \u3c 0.00002). A mathematical model, adopted to understand the mechanisms of negative food effects suggested that, lowering of permeability or solubility of the model compounds at the lower pH of the postprandial upper intestinal state may contribute to their negative food effects. Finally, this model was found to be useful in predicting negative food effects using in situ rat permeability values

Factors contributing to and predictive models for drugs exhibiting negative food effects of unknown mechanisms

Drugs exhibiting decreased extent of absorption in the fed state administration when compared to the fasted state administration are termed to exhibit a negative food effect. The known causes for negative food effects are luminal degradation and complexation to metal ions/Ca 2+ . For the drugs that do not undergo GI degradation and metal ion complexation, different factors were attributed to cause negative food effects, which are inconclusive. The objectives of this investigation were; to identify the physicochemical and physiological changes between fasted and fed states and their role in causing negative food effects; to develop an empirical model that correlates the biopharmaceutical properties of molecules to negative food effects; and translate the empirical model to a mechanistic model and explain the mechanisms of negative food effects for drugs that do not have clearly defined mechanisms of negative food effects. The important physicochemical change in the upper intestine was identified to be pH. The pH of the upper intestine in the fasted state is typically 6.5, whereas, the overall post-prandial pH after a standard meal in the duodenum is 5.4 (5.0 − 5.7) and the jejunal pH is 4.7 owing to the emptying of acidic chyme. Negative food effect drugs exhibited incomplete GI absorption, low Log P values and low apical to basolateral Caco-2 permeabilities. Acidic/basic drugs exhibiting either negative food effects or no food effects with a molecular size range of 200–450 Da and no physiological effects (such as secretions and motility) were selected from the literature. Multiple linear regression analysis using five drugs exhibiting negative food effects and seven drugs exhibiting no food effects indicated that, percent food effects correlated to acidic/basic dissociation constants (Ka/Kb) and to Caco-2 permeability (R 2 = 0.9114, Power ≈ 1 and p \u3c 0.00002). A mathematical model, adopted to understand the mechanisms of negative food effects suggested that, lowering of permeability or solubility of the model compounds at the lower pH of the postprandial upper intestinal state may contribute to their negative food effects. Finally, this model was found to be useful in predicting negative food effects using in situ rat permeability values

In vivo identification, survival, and functional efficacy of transplanted hepatocytes in acute liver failure mice model by FISH using Y-chromosome probe

Hepatocyte transplantation has excited much interest in lending temporary metabolic support to a failing liver following acute liver injury. The exact site from which they act and the clinical, biochemical, and histological changes in the recipient body following hepatocyte transplantation is yet to be worked out. The present study is an attempt to delineate location and function of transplanted hepatocytes and also the overall survival of these cells with a fluorescent in situ hybridization (FISH) technique using a Y-chromosome-specific probe in a carbon tetrachloride (CCl4)-induced mice model of fulminant hepatic failure. Fifty-five syngenic adult Swiss female mice of approximately the same age and body weight were divided into three groups. Group-1 (n=15), which received mineral oil, served as a negative control. Group-II (n=15) received CCl4 (3 mL/kg) 40% vol/vol in mineral oil, by gavage served as positive control for hepatic failure. Group-III (n=25) received intrasplenic transplantation of syngenic single cell suspension of hepatocytes in Hanks medium, after 30 h of CCl4 administration. Male Swiss adult mice (n=15) served as donors of hepatocytes. The overall survival of animals in groups I to III was 100, 0, and 70%, respectively, by 2 wk of the study period. Transplanted hepatocytes were identified by Periodic Acid Schiff (PAS) staining and confirmed with a FISH technique using the Y-chromosome probe. The majority of exogenously transplanted hepatocytes were found in the liver and spleen sections even after 1 wk of hepatocyte transplantation. Transplanted cells were mostly found to be translocated into the sinusoids of the liver. Transplanted hepatocytes were found to be beneficial as a temporary liver support in a failing liver, significantly improving the survival of the animals. In the present study, the FISH technique was used to unequivocally distinguish the transplanted cells from the host, and thus describes a model for studying the distribution and survival of the transplanted cells

Investigation of the differences in the pharmacokinetics of CYP2D6 substrates, desipramine and dextromethorphan in healthy African subjects carrying the allelic variants CYP2D6*17 and CYP2D6*29 when compared with normal metabolizers

This study investigated the differences in the pharmacokinetics (PK) of dextromethorphan and desipramine in African healthy volunteers to understand the effect of allelic variants of the human cytochrome-P450(CYP)2D6 enzyme namely, CYP2D6*1/*2 diplotypes, CYP2D6*17*17 and CYP2D6*29*29 genotypes. Overall, 28 adults were included through genotype screening into the three cohorts: CYP2D6*1/*2 (n=12), CYP2D6*17*17 (n=12), and CYP2D6*29*29 (n=4). Each subject received a single oral dose of dextromethorphan 30-mg syrup on Day 1 and desipramine 50-mg tablet on Day 8. The PK parameters, area under plasma concentration-time curve from time of dosing to time of last quantifiable concentration (AUClast) and extrapolated to infinity (AUCinf), and maximum plasma concentration (Cmax) were determined. For both dextromethorphan and desipramine, AUCinf and Cmax were higher in subjects of the CYP2D6*29*29 and CYP2D6*17*17 cohorts as compared with those reported in the CYP2D6*1/*2 diplotype cohort, and for normal metabolizers in literature. All PK parameters including AUCinf, Cmax, and elimination half-life followed a similar trend: CYP2D6*17*17 >CYP2D6*29*29 >CYP2D6*1/*2. The plasma and urinary drug/metabolite exposure ratios of both drugs were higher in subjects of the CYP2D6*17*17 and CYP2D6*29*29 cohorts when compared with those in the CYP2D6*1/*2 diplotype cohort. All adverse events were mild, except for one subject with CYP2D6*17*17 who had moderately severe headache with desipramine. These results indicated that subjects with CYP2D6*17*17 and CYP2D6*29*29 genotypes were 5–10 times slower metabolizers than those with CYP2D6*1/*2 diplotypes. These findings suggest that dose optimization may be required when administering CYP2D6 substrate drugs in African patients. Larger studies can further validate these findings