Moving Towards FAIR Data Practices in Pharmacy Education.

Pharmacy schools are generating significant amounts of data across the training continuum, including data about student selection, performance, and job placement. However, current data practices limit the Academy's ability to effectively leverage the vast amounts of data available within and across pharmacy institutions. To improve data practices and promote the quality and reusability of data, a set of guiding principles for data management and stewardship were developed and published in 2016.

Pharmacokinetics and Safety of Micafungin in Infants Supported With Extracorporeal Membrane Oxygenation.

Background: Candida is a leading cause of infection in infants on extracorporeal membrane oxygenation (ECMO). Optimal micafungin dosing is unknown in this population because ECMO can alter drug pharmacokinetics (PK).

Methods: To characterize micafungin pharmacokinetics and safety in infants on ECMO, we conducted an open-label pharmacokinetics trial.

Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors.

Tolvaptan is a selective vasopressin V2 receptor antagonist, approved in several countries for the treatment of hyponatremia and autosomal dominant polycystic kidney disease (ADPKD). No liver injury has been observed with tolvaptan treatment in healthy subjects and in non-ADPKD indications, but ADPKD clinical trials showed evidence of drug-induced liver injury (DILI). Although all DILI events resolved, additional monitoring in tolvaptan-treated ADPKD patients is required.

Characterization of the Cytochrome P450 epoxyeicosanoid pathway in non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is an emerging public health problem without effective therapies. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into bioactive epoxyeicosatrienoic acids (EETs), which have potent anti-inflammatory and protective effects. However, the functional relevance of the CYP epoxyeicosanoid metabolism pathway in the pathogenesis of NASH remains poorly understood.

Key Role for the 12-Hydroxy Group in the Negative Ion Fragmentation of Unconjugated C24 Bile Acids.

Host-gut microbial interactions contribute to human health and disease states and an important manifestation resulting from this cometabolism is a vast diversity of bile acids (BAs). There is increasing interest in using BAs as biomarkers to assess the health status of individuals and, therefore, an increased need for their accurate separation and identification. In this study, the negative ion fragmentation behaviors of C24 BAs were investigated by UPLC-ESI-QTOF-MS.

Prediction of Altered Bile Acid Disposition Due to Inhibition of Multiple Transporters: An Integrated Approach Using Sandwich-Cultured Hepatocytes, Mechanistic Modeling, and Simulation.

Transporter-mediated alterations in bile acid disposition may have significant toxicological implications. Current methods to predict interactions are limited by the interplay of multiple transporters, absence of protein in the experimental system, and inaccurate estimates of inhibitor concentrations. An integrated approach was developed to predict altered bile acid disposition due to inhibition of multiple transporters using the model bile acid taurocholate (TCA).

Hepatocellular Disposition and Transporter Interactions with Tolvaptan and Metabolites in Sandwich-Cultured Human Hepatocytes.

Tolvaptan is a selective V2-receptor antagonist primarily metabolized by CYP3A. The present study investigated the hepatocellular disposition of tolvaptan and the generated tolvaptan metabolites, DM-4103 and DM-4107, as well as the potential for drug-drug interaction (DDIs) with metabolic and transport proteins in sandwich-cultured human hepatocytes (SCHH). Tolvaptan was incubated with SCHH and quantified by LC-MS/MS.

Inhibition of Human Hepatic Bile Acid Transporters by Tolvaptan and Metabolites: Contributing Factors to Drug-Induced Liver Injury?

Tolvaptan is a vasopressin V(2)-receptor antagonist that has shown promise in treating Autosomal Dominant Polycystic Kidney Disease (ADPKD). Tolvaptan was, however, associated with liver injury in some ADPKD patients. Inhibition of bile acid transporters may be contributing factors to drug-induced liver injury.

Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis.

Background And Aims: The prevalence of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is increasing at an alarming rate. The role of bile acids in the development and progression of NAFLD to NASH and cirrhosis is poorly understood. This study aimed to quantify the bile acid metabolome in healthy subjects and patients with non-cirrhotic NASH under fasting conditions and after a standardized meal.

Fluconazole population pharmacokinetics and dosing for prevention and treatment of invasive Candidiasis in children supported with extracorporeal membrane oxygenation.

Candida infections are a leading cause of infectious disease-related death in children supported by extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK); thus, standard fluconazole dosing may result in suboptimal drug exposures. The objective of our study was to determine the PK of fluconazole in children on ECMO.

Toward predicting drug-induced liver injury: parallel computational approaches to identify multidrug resistance protein 4 and bile salt export pump inhibitors.

Drug-induced liver injury (DILI) is an important cause of drug toxicity. Inhibition of multidrug resistance protein 4 (MRP4), in addition to bile salt export pump (BSEP), might be a risk factor for the development of cholestatic DILI. Recently, we demonstrated that inhibition of MRP4, in addition to BSEP, may be a risk factor for the development of cholestatic DILI.

Species differences in hepatobiliary disposition of taurocholic acid in human and rat sandwich-cultured hepatocytes: implications for drug-induced liver injury.

The bile salt export pump (BSEP) plays an important role in bile acid excretion. Impaired BSEP function may result in liver injury. Bile acids also undergo basolateral efflux, but the relative contributions of biliary (CLBile) versus basolateral efflux (CLBL) clearance to hepatocellular bile acid excretion have not been determined.

Exploring BSEP inhibition-mediated toxicity with a mechanistic model of drug-induced liver injury.

Inhibition of the bile salt export pump (BSEP) has been linked to incidence of drug-induced liver injury (DILI), presumably by the accumulation of toxic bile acids in the liver. We have previously constructed and validated a model of bile acid disposition within DILIsym®, a mechanistic model of DILI. In this paper, we use DILIsym® to simulate the DILI response of the hepatotoxic BSEP inhibitors bosentan and CP-724,714 and the non-hepatotoxic BSEP inhibitor telmisartan in humans in order to explore whether we can predict that hepatotoxic BSEP inhibitors can cause bile acid accumulation to reach toxic levels.

Novel mechanism of impaired function of organic anion-transporting polypeptide 1B3 in human hepatocytes: post-translational regulation of OATP1B3 by protein kinase C activation.

The organic anion-transporting polypeptide (OATP) 1B3 is a membrane transport protein that mediates hepatic uptake of many drugs and endogenous compounds. Currently, determination of OATP-mediated drug-drug interactions in vitro is focused primarily on direct substrate inhibition. Indirect inhibition of OATP1B3 activity is under-appreciated.

Medication use and medical comorbidity in patients with chronic hepatitis C from a US commercial claims database: high utilization of drugs with interaction potential.

Background: With the advent of the direct-acting antiviral agents, significant drug-drug interaction (DDI) potential now exists for patients treated for chronic hepatitis C virus (HCV) infection. However, little is known about how often patients with HCV infection use medications that may interact with newer HCV treatments, especially those with cytochrome P450 3A (CYP3A) DDI potential.

Methods: Using a large US commercial insurance database, medication use and comorbidity burden were examined among adult patients with a chronic HCV diagnosis from 2006 to 2010.

Role of multidrug resistance-associated protein 4 in the basolateral efflux of hepatically derived enalaprilat.

Hepatic uptake and efflux transporters govern the systemic and hepatic exposure of many drugs and metabolites. Enalapril is a pharmacologically inactive prodrug of enalaprilat. Following oral administration, enalapril is converted to enalaprilat in hepatocytes and undergoes translocation into the systemic circulation to exert its pharmacologic effect by inhibiting angiotensin-converting enzyme.

Hepatocellular exposure of troglitazone metabolites in rat sandwich-cultured hepatocytes lacking Bcrp and Mrp2: interplay between formation and excretion.

Inhibition of bile acid transport by troglitazone (TGZ) and its major metabolite, TGZ sulfate (TS), may lead to hepatocellular accumulation of toxic bile acids; TS accumulation and hepatotoxicity may be associated with impaired TS biliary excretion. This study evaluated the impact of impaired transport of breast cancer resistance protein (Bcrp) and multidrug resistance-associated protein 2 (Mrp2) on the hepatobiliary disposition of generated metabolites, TS and TGZ glucuronide (TG). Sandwich-cultured hepatocytes (SCH) from Mrp2-deficient (TR(-)) rats in combination with Bcrp knockdown using RNA interference were employed.

Identification of hepatic phospholipidosis inducers in sandwich-cultured rat hepatocytes, a physiologically relevant model, reveals altered basolateral uptake and biliary excretion of anionic probe substrates.

Drug-induced phospholipidosis (PLD) is characterized by phospholipid accumulation within the lysosomes of affected tissues, resulting in lysosomal enlargement and laminar body inclusions. Numerous adverse effects and toxicities have been linked to PLD-inducing drugs, but it remains unknown whether drug-induced PLD represents a distinct toxicity or cellular adaptation. In silico and immortalized cellular models have been used to evaluate the PLD potential of new drugs, but these systems have some limitations.

An experimental approach to evaluate the impact of impaired transport function on hepatobiliary drug disposition using Mrp2-deficient TR- rat sandwich-cultured hepatocytes in combination with Bcrp knockdown.

Breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 2 (MRP2) are members of the ATP binding cassette (ABC) transporter family located in the canalicular membrane of hepatocytes that mediate biliary excretion of many drugs and endogenous compounds. BCRP and MRP2 have overlapping substrate profiles. Predicting drug disposition in the setting of altered transport function has important clinical significance.

Role of hepatic efflux transporters in regulating systemic and hepatocyte exposure to xenobiotics.

Hepatic efflux transporters include numerous well-known and emerging proteins localized to the canalicular or basolateral membrane of the hepatocyte that are responsible for the excretion of drugs into the bile or blood, respectively. Altered function of hepatic efflux transporters due to drug-drug interactions, genetic variation, and/or disease states may lead to changes in xenobiotic exposure in the hepatocyte and/or systemic circulation. This review focuses on transport proteins involved in the hepatocellular efflux of drugs and metabolites, discusses mechanisms of altered transporter function as well as the interplay between multiple transport pathways, and highlights the importance of considering intracellular unbound concentrations of transporter substrates and/or inhibitors.

Risk factors for development of cholestatic drug-induced liver injury: inhibition of hepatic basolateral bile acid transporters multidrug resistance-associated proteins 3 and 4.

Impaired hepatic bile acid export may contribute to development of cholestatic drug-induced liver injury (DILI). The multidrug resistance-associated proteins (MRP) 3 and 4 are postulated to be compensatory hepatic basolateral bile acid efflux transporters when biliary excretion by the bile salt export pump (BSEP) is impaired. BSEP inhibition is a risk factor for cholestatic DILI.

Hepatic basolateral efflux contributes significantly to rosuvastatin disposition II: characterization of hepatic elimination by basolateral, biliary, and metabolic clearance pathways in rat isolated perfused liver.

Basolateral efflux clearance (CLBL) contributes significantly to rosuvastatin (RSV) elimination in sandwich-cultured hepatocytes (SCH). The contribution of CLBL to RSV hepatic elimination was determined in single-pass isolated perfused livers (IPLs) from wild-type (WT) and multidrug resistance-associated protein 2 (Mrp2)-deficient (TR(-)) rats in the absence and presence of the P-glycoprotein and breast cancer resistance protein (Bcrp) inhibitor, elacridar (GF120918); clearance values were compared with SCH. RSV biliary clearance (CLBile) was ablated almost completely by GF120918 in TR(-) IPLs, confirming that Mrp2 and Bcrp primarily are responsible for RSV CLBile.

In vivo alterations in drug metabolism and transport pathways in patients with chronic kidney diseases.

Study Objective: This study was designed to prospectively evaluate the in vivo activities of drug transporters, metabolizing enzymes, and pharmacokinetics in patients with chronic kidney diseases (CKD) caused by glomerulonephritis and nonglomerular etiologies.

Design: A prospective study design.

Participants: Eighteen adults with CKD.

Hepatic basolateral efflux contributes significantly to rosuvastatin disposition I: characterization of basolateral versus biliary clearance using a novel protocol in sandwich-cultured hepatocytes.

Transporters responsible for hepatic uptake and biliary clearance (CLBile) of rosuvastatin (RSV) have been well characterized. However, the contribution of basolateral efflux clearance (CLBL) to hepatic and systemic exposure of RSV is unknown. Additionally, the appropriate design of in vitro hepatocyte efflux experiments to estimate CLBile versus CLBL remains to be established.

Determination of intracellular unbound concentrations and subcellular localization of drugs in rat sandwich-cultured hepatocytes compared with liver tissue.

Prediction of clinical efficacy, toxicity, and drug-drug interactions may be improved by accounting for the intracellular unbound drug concentration (C(unbound)) in vitro and in vivo. Furthermore, subcellular drug distribution may aid in predicting efficacy, toxicity, and risk assessment. The present study was designed to quantify the intracellular C(unbound) and subcellular localization of drugs in rat sandwich-cultured hepatocytes (SCH) compared with rat isolated perfused liver (IPL) tissue.