Development of a Physiologically Based Pharmacokinetic Model for Prediction of Ethanol Concentration-Time Profile in Different Organs

A physiologically based pharmacokinetic (PBPK) modeling approach was used to simulate the concentration-time profile of ethanol (EtOH) in stomach, duodenum, plasma and other tissues upon consumption of beer and whiskey under fasted and fed conditions. Methods: A full PBPK model was developed for EtOH using the advanced dissolution, absorption and metabolism (ADAM) model fully integrated into the Simcyp Simulator® 15 (Simcyp Ltd., Sheffield, UK). The prediction performance of the developed model was verified and the EtOH concentration-time profile in different organs was predicted. Results: Simcyp simulation showed ≤ 2-fold difference in values of EtOH area under the concentration-time curve (AUC) in stomach and duodenum as compared to the observed values. Moreover, the simulated EtOH maximum concentration (Cmax), time to reach Cmax (Tmax) and AUC in plasma were comparable to the observed values. We showed that liver is exposed to the highest EtOH concentration, faster than other organs (Cmax = 839.50 mg/L and Tmax = 0.53 h), while brain exposure of EtOH (AUC = 1139.43 mg·h/L) is the highest among all other organs. Sensitivity analyses (SAs) showed direct proportion of EtOH rate and extent of absorption with administered EtOH dose and inverse relationship with gastric emptying time (GE) and steady-state volume of distribution (Vss). Conclusions: The current PBPK model approach might help with designing in vitro experiments in the area of alcohol organ damage or alcohol-drug interaction studies

Physicochemical Properties, Biotransformation, and Transport Pathways of Established and Newly Approved Medications: A Systematic Review of the Top 200 Most Prescribed Drugs vs. the FDA-Approved Drugs Between 2005 and 2016

Background: Enzyme-mediated biotransformation of pharmacological agents is a crucial step in xenobiotic detoxification and drug disposition. Herein, we investigated the metabolism and physicochemical properties of the top 200 most prescribed drugs (established) as well as drugs approved by the US Food and Drug Administration (FDA) between 2005 and 2016 (newly approved). Objective: Our objective was to capture the changing trends in the routes of administration, physicochemical properties, and prodrug medications, as well as the contributions of drug-metabolizing enzymes and transporters to drug clearance. Methods: The University of Washington Drug Interaction Database (DIDB®) as well as other online resources (e.g., CenterWatch.com, Drugs.com, DrugBank.ca, and PubChem.ncbi.nlm.nih.gov) was used to collect and stratify the dataset required for exploring the above-mentioned trends. Results: Analyses revealed that ~ 90% of all drugs in the established and newly approved drug lists were administered systemically (oral or intravenous). Meanwhile, the portion of biologics (molecular weight \u3e 1 kDa) was 15 times greater in the newly approved list than established drugs. Additionally, there was a 4.5-fold increase in the number of compounds with a high calculated partition coefficient (cLogP \u3e 3) and a high total polar surface area (\u3e 75 Å2) in the newly approved drug vs. the established category. Further, prodrugs in established or newly approved lists were found to be converted to active compounds via hydrolysis, demethylases, and kinases. The contribution of cytochrome P450 (CYP) 3A4, as the major biotransformation pathway, has increased from 40% in the established drug list to 64% in the newly approved drug list. Moreover, the role of CYP1A2, CYP2C19, and CYP2D6 were decreased as major metabolizing enzymes among the newly approved medications. Among non-CYP major metabolizers, the contribution of alcohol dehydrogenases/aldehyde dehydrogenases (ADH/ALDH) and sulfotransferases decreased in the newly approved drugs compared with the established list. Furthermore, the highest contribution among uptake and efflux transporters was found for Organic Anion Transporting Polypeptide 1B1 (OATP1B1) and P-glycoprotein (P-gp), respectively. Conclusions: The higher portion of biologics in the newly approved drugs compared with the established list confirmed the growing demands for protein- and antibody-based therapies. Moreover, the larger number of hydrophilic drugs found in the newly approved list suggests that the probability of toxicity is likely to decrease. With regard to CYP-mediated major metabolism, CYP3A5 showed an increased involvement owing to the identification of unique probe substrates to differentiate CYP3As. Furthermore, the contribution of OATP1B1 and P-gp did not show a significant shift in the newly approved drugs as compared to the established list because of their broad substrate specificity

Determination Of The Factors Affecting The Survival Rate Of Patients With Lung Cancer Using Bayesian Model; Historical Cohort

Introduction: Gastric cancer is one of the most common and deadly cancers in Iran. Gastric cancer is highly dependent on nutritional factors and geographical location. Therefore, the aim of this study was to evaluate the effect of nutritional factors on gastric cancer in Hamadan-Iran. Method: This study was performed as a matched case-control study that each case had two controls that matched with cases in age (±5 years) and gender at Diagnostic and Treatment Center of Mahdieh in Hamedan, Iran. First and second control groups contain persons with and without family history of cancer, respectively. Information of nutritional, epidemiological and confounding variables were collected for 100 cases and 200 controls. Controls from hospital samples, friends and acquaintances of the case group were selected. Data were collected using a researcher-made questionnaire. Data were analyzed using conditional logistic regression by Bayesian method. Results: Findings showed that, compared with individuals in the case group with the family history group with factors hot food (OR=2.35, 0.95%CrI=(1.82,5.19)), black tea (OR=1.60, 0.95%CrI (1.44,1.72)) cigarettes (OR=2.13, 0.95%CrI=(1.68,2.96)), red meat (OR=4.28, 0.95%CrI=(3.11,8.37)), residence (OR=3.15, 0.95%CrI= (1.62,5.65)), fruit (OR=0.75, 0.95% CrI=(0.63,0.83)) and vegetables (OR=0.76, 0.95%CrI=(0.59,0.85)) there was a strong statistical correlation. The results were also valid for the second control group. Conclusion: The study showed that many controllable nutritional factors in Hamadan affect the incidence of gastric cancer. It is recommended that policymakers and managers inform the public about the risk factors and prevention of gastric cancer through the publication of brochures, television and newspapers

A deeper insight into how GABA-B receptor agonism via baclofen may affect alcohol seeking and consumption: lessons learned from a human laboratory investigation

Previous studies suggest that GABA-B receptor agonism may represent an effective pharmacological approach to treat addictive disorders. Baclofen is a selective GABA-B receptor agonist which has been investigated as a potential treatment for alcohol use disorder. However, research is needed to understand the biobehavioral mechanisms underlying baclofen’s effect on alcohol use. In the present randomized, double-blind, placebo-controlled study, thirty-four alcohol-dependent individuals were randomized to receive baclofen (30 mg/d) or placebo for a week, and then participated in a laboratory experiment consisting of three procedures: alcohol cue-reactivity, priming, and self-administration. During the experiment, craving and other subjective responses to alcohol were assessed, and blood samples were collected for pharmacokinetic measurements. The effects of baclofen on the relationships between different alcohol-related laboratory parameters were investigated. Baclofen pharmacokinetic parameters and their correlations with behavioral measures were also examined. Results showed that baclofen disrupted the link between alcohol priming and self-administration, as indicated by significant interaction effects between drug condition (baclofen vs. placebo) and some of the priming variables (alcohol craving: F3,9 = 6.03, p = 0.01; alcohol sedation: F3,6 = 7.16, p = 0.01) on the total amount of alcohol self-administered. Considerable interindividual variability in baclofen pharmacokinetic parameters was observed. Maximum plasma concentrations of baclofen negatively correlated with cue-induced alcohol craving (r = −0.57, p = 0.03) and priming-induced ratings of ‘like more’ (r = −0.59, p = 0.02). In conclusion, baclofen may work by dissociating the link between an initial drink (priming) and subsequent alcohol consumption (self-administration). Considerable pharmacokinetic variability is an important factor to take into account when employing baclofen as a treatment for alcohol use disorder