Intro -- Atkinson's Principles of Clinical Pharmacology -- Copyright -- Contents -- Contributors -- Preface to the first edition -- Preface to the fourth edition -- Chapter 1: Introduction to clinical pharmacology -- Background -- Optimizing use of existing medicines -- Evaluation and development of medicines -- Pharmacokinetics -- The concept of clearance -- Clinical estimation of renal function -- Dose-related toxicity often occurs when impaired renal function is unrecognized -- References -- Additional sources of information -- Chapter 2: Clinical pharmacokinetics -- The target concentration strategy -- Monitoring serum concentrations of digoxin as an example -- General indications for drug concentration monitoring -- Concepts underlying clinical pharmacokinetics -- Initiation of drug therapy (concept of apparent distribution volume) -- Continuation of drug therapy (concepts of elimination half-life and clearance) -- Elimination half-life -- Elimination clearance -- Drugs not eliminated by first-order kinetics -- Mathematical basis of clinical pharmacokinetics -- First-order elimination kinetics -- Concept of elimination half-life -- Relationship of k to elimination clearance -- Cumulation factor -- The plateau principle -- Application of Laplace transforms to pharmacokinetics -- References -- Study problems -- Chapter 3: Compartmental analysis of drug distribution -- Fit-for-purpose modeling of drug distribution -- Physiological significance of drug distribution volumes -- Physiological basis of multicompartmental models of drug distribution -- Formulation of multicompartmental models -- Basis of multicompartmental structure -- Mechanisms of transcapillary exchange -- Clinical consequences of different drug distribution patterns -- Drugs with faster elimination than distribution -- Estimating model parameters from experimental data.

Derivation of equations for a two-compartment model -- Calculation of rate constants and compartment volumes from data -- Different estimates of apparent volume of distribution -- References -- Study problems -- Chapter 4: Drug absorption and bioavailability -- Drug absorption -- Metabolism by intestinal bacteria -- Presystemic elimination -- Drug-drug and food-drug interactions -- Bioavailability -- Absolute bioavailability -- Relative bioavailability -- In vitro prediction of bioavailability -- Kinetics of drug absorption after oral administration -- Time to peak level -- Value of peak level -- Use of convolution/deconvolution to assess in vitro-in vivo correlations -- References -- Study problems -- Chapter 5: Effect of kidney disease on pharmacokinetics -- Drug dosing in patients with impaired kidney function -- Effects of kidney disease on renal drug elimination mechanisms -- Excretion mechanisms: Filtration and secretion -- Reabsorption mechanisms -- Renal metabolism -- Analysis and interpretation of renal excretion data -- Effects of impaired kidney function on nonrenal clearance pathways -- Nonrenal metabolism -- Nonrenal transport -- Potential mechanisms of altered nonrenal clearance -- Effects of kidney disease on drug distribution -- Plasma protein binding of acidic drugs -- Plasma protein binding of basic and neutral drugs -- Tissue binding of drugs -- Effects of kidney disease on drug absorption -- Study problem -- References -- Chapter 6: Pharmacokinetics in patients requiring renal replacement therapy -- Kinetics of intermittent hemodialysis -- Solute transfer across dialyzing membranes -- Calculation of dialysis clearance -- Patient factors affecting hemodialysis of drugs -- Hemodynamic changes during Dialysis -- Kinetics of CRRT and sustained renal replacement therapy -- Clearance by continuous hemofiltration.

Clearance by continuous hemodialysis and SLED -- Extracorporeal clearance during continuous renal replacement therapy -- Clinical considerations -- Drug dosing guidelines for patients requiring renal replacement therapy -- Extracorporeal therapy of patients with drug toxicity -- References -- Chapter 7: Effect of liver disease on pharmacokinetics -- Physiologic determinants of hepatic drug clearance -- Hepatic elimination of drugs -- Restrictively metabolized drugs (ER0.3) -- Effect of changes in protein binding on hepatic clearance -- Effect of changes in intrinsic clearance on hepatic drug clearance -- Drugs with an intermediate extraction ratio (0.3ER0.7) -- Nonrestrictively metabolized drugs (ER0.70) -- Biliary excretion of drugs -- Enterohepatic circulation -- Effects of liver disease on pharmacokinetics -- Acute hepatitis -- Chronic liver disease and cirrhosis -- Pharmacokinetic consequences of liver cirrhosis -- Influence of portosystemic shunting on nonrestrictively metabolized drugs -- Consequences of decreased protein binding -- Consequences of hepatocellular changes -- Use of therapeutic drugs in patients with liver disease -- Classification schemes for liver function -- FDA guidance for industry on pharmacokinetic studies in patients with impaired hepatic function -- Other tools for the assessment of liver function -- Effects of liver disease on the hepatic elimination of drugs -- Correlation of laboratory tests with drug metabolic clearance -- Use of probe drugs to characterize hepatic drug clearance -- Effects of liver disease on the renal elimination of drugs -- Effects of liver disease on patient response -- Modification of drug therapy in patients with liver disease -- References -- Chapter 8: Noncompartmental and compartmental approaches to pharmacokinetic data analysis -- Introduction.

Kinetics, pharmacokinetics, and pharmacokinetic parameters -- Kinetics and the link to mathematics -- The pharmacokinetic parameters -- Accessible pool parameters -- System parameters -- Moments -- Noncompartmental analysis -- Noncompartmental model -- Kinetic parameters of the noncompartmental model -- The single accessible pool model -- The two accessible pool model -- Estimating the kinetic parameters of the noncompartmental model -- Estimating AUC and AUMC using sums of exponentials -- Estimating AUC and AUMC using other functions -- Estimating t1tnC(t)dt and t1tntC(t)dt -- Extrapolating from tn to infinity -- Estimating AUC and AUMC from 0 to infinity -- Compartmental analysis -- Definitions and assumptions -- Linear, constant coefficient compartmental models -- Parameters estimated from compartmental models -- Experimenting on compartmental models: Input and measurements -- Nonlinearities in compartmental models -- Calculating pharmacokinetic parameters from a compartmental model -- Model parameters -- Residence time calculations -- Noncompartmental versus compartmental models -- Models of data vs. models of system -- The equivalent sink and source constraints -- Linearity and time invariance -- Recovering pharmacokinetic parameters from compartmental models -- Conclusion -- References -- Chapter 9: Population pharmacokinetics -- Introduction -- Analysis of pharmacokinetic data -- Structure of pharmacokinetic models -- Fitting individual data -- Population pharmacokinetics -- Population analysis methods -- The na�ive pooled data method -- The two-stage method -- Nonlinear mixed effects modeling method -- Model comparison -- Model evaluation -- Model applications -- Mirogabalin case study -- Milademetan case study -- Conclusions -- References -- Chapter 10: Pathways of drug metabolism -- Introduction.

The chemistry and enzymology of drug metabolism -- Oxidations and nonconjugation reactions -- Cytochrome P450 monooxygenases -- Cytochrome P450 families -- The CYP3A family -- The CYP2C family -- The CYP2D6 family -- The CYP 1A family -- Non-CYP oxidations -- Flavin-containing monooxygenases -- Monoamine oxidases -- Molybdenum-containing oxidases -- Esterases -- Epoxide hydrolases -- Conjugation reactions -- Glucuronosyl transferases -- Sulfotransferases -- Acetyl transferases -- Methyltransferases -- Glutathione transferases -- References -- Chapter 11: Bioanalytical methods: Technological platforms and method validation -- Technological platforms of bioassays -- High performance/pressure liquid chromatography -- Chromatographic column -- Mobile phase -- Detectors -- Alternative chromatographic approaches -- Gas chromatography -- LC-MS/MS and high resolution mass spectrometry (HRMS) -- Internal standards -- Accelerator mass spectrometry -- Immunoassays -- Polymerase chain reaction assays -- Method validation -- Sample analysis -- Cross-validation -- Case examples -- Interference -- Establishing assay range -- Impact of sample handling or instability -- Assessing results from two assays: Cross-validation -- Conclusion -- References -- Chapter 12: Clinical pharmacogenetics -- Introduction -- General principles -- Pharmacogenetics and pharmacogenomics -- Human genetics -- Indications for performing pharmacogenetic studies -- Genetic analysis techniques and informatics -- Examples of clinically relevant genetic polymorphisms -- Genetic variation in Phase I metabolic pharmacogenes -- CYP2B6 -- CYP2C9 -- CYP2C19 -- CYP2D6 -- CYP3A4 and CYP3A5 -- Genetic variation in Phase II metabolic pharmacogenes -- Thiopurine S-methyltransferase (TPMT) -- N-Acetyltransferase 2 (NAT2) -- Target/efficacy pharmacogenetics.

Vitamin K epoxide reductase complex, subunit 1 (VKORC1).

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Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, 2022. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries.