Drug metabohsm

When the drug concentrations are below the K, Clj is essentially independent of drug concentration. The processes of drug metaboHsm are similar to other en2ymat-ic processes. For instance most oxidative processes (cytochrome P450) obey Michaelis-Menten kinehcs ... 

This book is a reflection of today s knowledge in drug metaboHsm and pharmacokinetics. However, there is more to come, when in the future the role and funcHon of various transporters is better understood and predictive methods have matured further. 

Explore drug metabohsm and drug interactions Estimate activity Drug interaction studies... 

Since disease processes lead to protein changes, it is of paramount importance to consider the relationship between disease and therapy at the protein level (Anderson and Anderson 1998). The objective of modern pharmacoproteomics is the identification of phenotypic differences in drug metabohsm or response and the subsequent examination of candidate proteins for variations that underUe the observed phenotypes. Instead of focusing on a few protein targets, pharmacoproteomics takes a more global approach in order to capture complicated patterns of protein expression (Anderson and Anderson 1998 Petricoin III et al. 2002). 

Watkins, P. B. Role of cytochromes P450 in drug metabohsm and hepatotoxicity. Semin. Liver Dis. 10, 235,1990. 

The evolution observed in the techniques chosen for analysis also provides a clear indication of these changes in place of the RIA that was widely used in early times of hair analysis, but has become obsolete since it cannot be practically applied to unequivocal confirmations or study of drug metabohsms, GC/MS is presently employed by almost all investigators as the unique method of reference — for routine as well as for experimental purposes. 

Recent advances in mass spectrometry have rendered it an attractive and versatile tool in industrial and academic research laboratories. As a part of this rapid growth, a considerable body of hterature has been devoted to the apph-cation of mass spectrometry in clinical studies. In concert with separation techniques such as hquid chromatography, mass spectrometry allows the rapid characterization and quantitative determination of a large array of molecules in complex mixtures. Herein, we present an overview of the above techniques accompanied with several examples of the use of liquid chromatography-tandem mass spectrometry in pharmacokinetics/drug metabohsm assessment during drug development. 

Biochemical Functions. Ascorbic acid has various biochemical fimctions, involving, for example, coUagen synthesis, immune fimction, drug metabohsm, folate metabolism, cholesterol catabolism, iron metabolism, and carnitine biosynthesis. Clear-cut evidence for its biochemical role is available only with respect to coUagen biosynthesis (hydroxylation of prolin and lysine). In addition, ascorbic acid can act as a reducing agent and as an effective antioxidant. Ascorbic acid also interferes with nitrosamine formation by reacting directly with nitrites, and consequently may potentially reduce cancer risk. 

Buchert, E. Woosley, R.L. Chnical implications of variable antiarrythmic drug metabohsm. Pharmacogenetics 1992, 2, 2-11. 

Wei P, Zhang J, Egan-Hafley M, et al. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabohsm. Nature 2000 407 920-3. 

Synold TW, Dussault I, Forman BM. The orphan nuclear receptor SXR coordi-nately regulates drug metabohsm and efflux. Nat Med 2001 7 584-90. 

The enzyme is present in two different forms. A membrane-bound 300 amino acid form is located mainly in the endoplasmic reticulum and outer mitochondrial membrane. The membrane form has a role in desaturation and elongation of fatty acids, cholesterol biosynthesis, and drug metabohsm. 

The liver is the principal organ responsible for xenobiotic metabolism. One of its major roles is to convert lipophilic nonpolar molecules to more polar water-soluble forms. The drug molecule (a xenobiotic) can be modified by phase I reactions, which alter chemical structure by oxidation, reduction, or hydrolysis or by phase II reactions, which conjugate the drug (glucuronidation or sulfation) to create more water-soluble forms. Typically, both phase I and phase II reactions occur. Most drug metaboHsm takes place in the microsomal fraction of the hepatocytes, where many environmental chemicals and endogenous biochemicals (xeno-biotics) are also processed by the same mechanisms. 

Meyer UA, Zanger UM. Molecular mechanisms of genetic polymorphisms of drug metabohsm. Annu Rev Pharmacol Toxicol 1997 37 269-96. 

Nebert DW> Dieter MZ. The evolution of drug metabohsm. Pharmacology 2000 61 124-35. 

Josephy, P. D., Guengerich, E. R, Miners, J. O. Phase I and phase II drug metabohsm terminology that we should phase out Drug Metab. Rev. 2005, 37, 575. 

Kearns GL. Hepatic drug metabohsm in cystic fibrosis Recent developments and future directions. Ann Pharmacother 1993 27 74-79. 

Nassar, A.E. et al., Liquid chromatography-accurate radioisotope counting and microplate scintillation counter technologies in drug metabohsm studies, J. Chromatogr. Sci., 42(7), 348, 2004. 

This chapter will look particularly at in vitro assays for phase I drug metaboHsm mediated by Hver cytochrome P450s and at a new assay for genotoxicology, Green-Screen GC, being offered through Met-tox (BTG s ADMET platform business). 

Although studies have shown that hepatic drug metabolism is predominantly decreased in patients with end stage renal disease, prediction of the effect of renal impairment on drug metabohsm is difficult. One reason for this is that the rates of metabolism for most drugs vary so widely from person to person because of genetic factors [47,48] that a disease state like renal failure only makes a small contribution, if any, to the interindividual variation in drug metabohsm rates. 

Chapter 12 Drug-Drug Interactions with an Emphasis on Drug Metabohsm and Transport... 

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