Pharmacokinetic Studies of Drugs

TABLE 7-6. Statistical Analysis of Back-Calculated Normalized Ketotifen Concentrations of the Calibration Standards in lliiiiiaii Plasma 

Source Reprinted from reference 98, with permission of Elsevier Science. 

2 On-Line Sample Preparation for Biological Fluids. There is a continuing demand for high-throughput bioanalytical method based on 

TABLE 7-7. Calibration Concentrations (n = 2) Back-Calcnlated from the Ratio of the Peak Areas of ET-743 and ET-729 

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Another related technique, MRM, involves a MS/MS experiment that is often performed in a triple quadrupole mass spectrometer. Typically, Q1 is set to pass the parent ion and Q2 is used as a colhsion cell to fragment the parent ion. The third quadrupole is to transmit only diagnostic product ion from the parent ion. The advantage is the increased specihcity from MS/MS experiment. MRM provides the highest-duty cycle scan in a triple quadrupole and is widely used in quantitating multiple analytes in a complex matrix (examples are given in the section on pharmacokinetic studies of drugs). 

The major food producing crustaceans that are presently aquacultured are various shrimp species, crayfish and lobsters (77). Pharmacokinetic studies of drugs have been done so far only in the lobster, but studies of the pharmacokinetics and metabolism of some agricultural chemicals have been conducted in crab and crayfish species. 

As with GC, HPLC can be used qualitatively for identification or quantitatively to determine how much of a compound is present. Some examples of the use of HPLC in qualitative work include identification of impurities and toxicity screening. Some examples of the use of HPLC in quantitative work are drug testing in athletes and in sports supplements, pharmacokinetic studies of drugs pharmaceutical assays and fatty acid analysis. ... 

An automated sequential trace enrichment dialyzer and gradient HPLC system is proposed for pharmacokinetic studies of drugs and their metabolites.The dialyzer is essential in the determination of pharmaceutical compounds from tablets and biological fluids (e.g., blood). By its incorporation into the conduits of a SIA system and coupling with the HPLC, the objectivity and reproducibility of the measurements were increased. 

Han Nl, Lee YS, Choi H, Choi JY, Yun SK, Cho SH, Han JY, Yang JM, Ahn BM, Choi SW, Lee CD, Cha SB, Sun HS, Park DH (2002) PCNA expression and electron microscopic study of acinus-forming hepatocytes in chronic hepatitis B. Korean J Intern Med 17 100-106 Herve F, Urien S, Albengres E, Duche JC, TiUement IP (1994) Drug binding in plasma. A summary of recent trends in the study of drug and hormone binding. Qin Pharmacokinet 26 44-58... 

Poulin P, Theil FP. Prediction of pharmacokinetics prior to in vivo studies. II. Generic physiologically based pharmacokinetic models of drug disposition. J Pharm Sci 2002 May 91(5) 1358-70. 

A second area of drug discovery and development in which enzyme reactions play a critical role is in the study of drug metabolism and pharmacokinetics. The elimination of xenobiotics, including drug molecules, from systemic circulation is driven by metabolic transformations that are entirely catalyzed by enzymes. Table 1.2 lists some of the enzyme-catalyzed transformations of xenobiotics that commonly contribute to drug molecule elimination. These biotransformation reactions... 

Lin, J.H. and Rodrigues, A.D. 2001. In vitro models for early studies of drug metabolism. In Pharmacokinetic Optimization in Drug Research Biological, Physicochemical and Computational Strategies. Testa, B. et al., Eds., Wiley, New York, p. 217. 

A phase I clinical and pharmacokinetic study of PKl comprising doxorubicin covalently bound to N-(2-hydroxypropyl)-methacrylamide copolymer by a peptidyl linker, was carried out in 36 patients with refractory or resistant cancers [94], PKl demonstrated anti-tumour activity, and that polymer-drug conjugation decreased doxorubicin dose-limiting toxicities. Phase II studies are in progress. 

The first factor lead to the studies of drug interactions. These had been preceded by studies of factors that modified drug metabolism and were focused primarily on pharmacokinetic drug interactions... 

The NME can now be administered to humans. The first step in clinical evaluation is one or more phase I studies designed to assess the drug s safety and pharmacokinetic profile. Phase I studies usually involve a small number of healthy volunteers who are closely monitored after receiving escalating doses of the drug candidate. Phase I studies of drugs for cancer or HIV infection must be carried out in patients, not in healthy subjects. Ordinarily, until more information is available, the minimum dose to induce side effects is stipulated as the upper dose limit for subsequent administration to human subjects. 

Table 1 Case Reports and Pharmacokinetic Study of Interactions Between Garlic and Prescription Drugs... 

Pharmacokinetics and pharmacodynamics form the two major branches of pharmacoiogy. Pharmacokinetics is the study of drug disposition and deais with the processes of absorption, distribution, metaboiism and eiimination. Pharmacodynamics is concerned with the reiationship between the concentration of a drug and its effect. Put another way, pharmacodynamics is what a drug does to the body whiie pharmacokinetics is what the body does to a drug. This chapter wiii cover the generai principies reiating to these processes, and deveiop some of the principies that describe their kinetics and dynamics. 

Vasey, P. A., Kaye, S. B., Morrison, R., et al. Phase I clinical and pharmacokinetic study of PK1 [lV-(2-hydroxypropyl)methacrylamide copolymer doxorubicin] First member of a new class of chemotherapeutic agents-drug-polymer conjugates. Cancer Research Campaign Phase I/II Committee. Clin. Cancer Res. 5(l) 83-94. 1999. 

Baillie, T. A. 1992. Advances in the application of mass spectrometry to studies of drug metabolism, pharmacokinetics and toxicology. Int. J. Mass Spectrom. Ion Proc., 118/119, 289-314. 

Robust and rugged LC-MS/MS methods are essential in support of drug discovery, toxicology studies, and clinical trials, for the data generated from these bioanalytical methods is used to evaluate the bioavailability, bioequivalence, toxicokinetic, and pharmacokinetic parameters of drug candidates. Thus, it is critical to invest significant thought and effort in the method development process [25-27], Fast sample... 

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