Transporters and Drug-Metabolizing Enzymes in Drug Toxicity. Albert P. Li
Introduction 15.2 Application of the ECM to Estimate Kpuu Liver 15.3 Relevant Concentrations for the DILI Risk Assessment 15.4 Assessing the DIC Risk Using ECM‐Based Unbound Intrahepatic Concentrations and Accounting for BSEP Inhibition as a Single Mechanism 15.5 Assessing the DILI Risk Using the “1/R‐Value Model” to Account for the Inhibition of Multiple Pathways 15.6 Discussion and Outlook References
10 Index
List of Tables
1 Chapter 2Table 2.1 Genetic diseases related to hepatic transporters.Table 2.2 Selected reports for the association between gene variations and dr...
2 Chapter 3Table 3.1 A summary of the key mechanisms of drug‐induced toxicity for the 12...
3 Chapter 5Table 5.1 Associations between polymorphisms affecting drug metabolism and DI...Table 5.2 Summary of selected NAT2 candidate gene studies concerned with ison...
4 Chapter 7Table 7.1 MS applications in detection of GSH trapped reactive metabolites.
5 Chapter 10Table 10.1 Major hepatic bile acid transporters and their bile salt substrate...Table 10.2 A non‐exhaustive list of non‐cholestatic and cholestatic drugs wit...
6 Chapter 11Table 11.1 Selected renal transporters on apical and basolateral membrane of ...Table 11.2 Relativein vitro inhibition on human OCT2, MATE1, and MATE2K by se...Table 11.3 Effects of selective renal transporter inhibition on metformin pha...Table 11.4 Effects of selective renal transporter inhibition on creatinine ch...Table 11.5 Examples of drug‐induced nephrotoxicity and biomarkers used to ass...
7 Chapter 12Table 12.1 ABC and SLC transporters in CNS fluid barriers.Table 12.2 Physicochemical and binding properties of selected anti‐histamines...Table 12.3 Selected opioids and drug transporter interactions at the BBB.
8 Chapter 13Table 13.1 Partial list of ototoxic drugs.
9 Chapter 15Table 15.1 In vitro enzyme/transporter inhibition constants and human drug exposu...Table 15.2 1/R‐assessment analysis following single or parallel worst‐case pa...
List of Illustrations
1 Chapter 1Figure 1.1 Schematic illustration of the Multiple Determinant Hypothesis of ...
2 Chapter 2Figure 2.1 The physiological process of drug metabolism and transport and th...Figure 2.2 The most frequent human P450 enzymes involved in metabolism of cl...Figure 2.3 Some typical structure alerts for formation of reactive metabolit...Figure 2.4 Hepatic proteins involved in drug, bilirubin, and bile acid trans...
3 Chapter 3Figure 3.1 Chemical structure of the 12 toxic drugs reviewed.
4 Chapter 6Figure 6.1 Chemical structures of carboxylic acid‐containing drugs and compo...Figure 6.2 (a) Benzoic acid β‐D‐acyl glucuronide formation catalyzed by UGT ...Figure 6.3 Instability of carboxylic acid‐containing drug acyl glucuronide b...Figure 6.4 Reactivity of carboxylic acid‐containing drug or compound acyl‐Co...
5 Chapter 7Figure 7.1 Some common conjugations with glutathione (GSH) (i) halides; (ii)...Figure 7.2 Characteristic fragment ions of glutathione used in the MS applic...Figure 7.3 Assay strategy: Reactive intermediates (labeled as R) are capture...Figure 7.4 Data analysis of Raloxifene‐GSH adducts. (a) XoPI m/z of 272.0888...Figure 7.5 Chemical structure of glutathione derivatives.Figure 7.6 Proposed the formation of cyclized Cys‐Gly adducts when incubated...Figure 7.7 Reactive metabolite decision tree during the candidate identifica...
6 Chapter 8Figure 8.1 In vitro hepatotoxicity assay for species comparison. The assay i...Figure 8.2 Evaluation of inter‐individual difference in drug toxicity with h...Figure 8.3 Cytotoxic Metabolic Pathway Identification Assay (CMPIA) and Meta...Figure 8.4 MetMax™ Cryopreserved Human Hepatocytes (MMHH) Metabolic Activati...Figure 8.5 ROS/ATP AUC Human Hepatocyte Assay for DILI Drugs. This assay, co...Figure 8.6 Long‐term cultured 999Elite™ cryopreserved human hepatocytes. The...Figure 8.7 In vitro hepatotoxicity with human hepatocytes. Human hepatocyte ...Figure 8.8 Integrated Discrete Multiple Organ Coculture. A photograph of the...Figure 8.9 Protoxicant assay with IdMOC. The IdMOC system allows incorporati...Figure 8.10 Classification of toxicants based on metabolic activation. A met...
7 Chapter 9Figure 9.1 Schematic diagram depicting the membrane vesicle assay for BSEP t...Figure 9.2 Schematic depicting the working principle of B‐CLEAR® method...Figure 9.3 Schematic diagram coupling the experimental transport protocol (a...Figure 9.4 Diagram depicting bile acid accumulation as a key submodel in the...
8 Chapter 10Figure 10.1 Schematic illustration of transporters control bile flow in the ...Figure 10.2 Transcriptional regulation of bile salt export pump (BSEP) by FX...
9 Chapter 11Figure 11.1 Expression of major drug transporters in kidney proximal tubular...Figure 11.2 Inhibition of organic cation transporters in the renal tubular c...
10 Chapter 12Figure 12.1 Schematic of blood–brain (a) and blood–cerebral spinal (b) barri...Figure 12.2 BOILED‐Egg model depicting the lipophilicity (WLOGP) and topogra...
11 Chapter 13Figure 13.1 General anatomy of the inner ear.
12 Chapter 14Figure 14.1 Schematic diagram of the hepatobiliary transport and metabolism ...Figure 14.2 PBPK model analysis of pravastatin [16]. (a) Diagram of the stru...Figure 14.3 Basic concept of a virtual clinical trial (VCT).Figure 14.4 VCT of docetaxel to estimate the impact of OATP1B3 and MRP2 on t...Figure 14.5 VCT of oseltamivir and its active metabolite, Ro 64‐0802, to eva...Figure 14.6 VCT of irinotecan to analyze the impact of genetic polymorphisms...
13 Chapter 15Figure 15.1 Cell stress perturbations in the liver are frequently the result...Figure 15.2 Drug classification according to ECM (Eq. (15.1)) and expected i...Figure 15.3 BSEP Kiu/I ratios vs DIC relationships for the dataset summarize...Figure 15.4 1/R‐ and SMapp‐value (according to Eq. (15.14)) vs DILI relation...
Guide
4 Preface
5
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