PRINCIPAL METABOLIC PATHWAYS

In humans, the principal metabolic pathway of the anti-inflammatory agent indomethacin (4.92) proceeds through O-demethylation to yield 4.94,... 

When working with non-radiolabeled drugs the major challenge is to find metabolites in the biological matrices. Because the enzymes responsible for metabolism are quite well characterized metabolic changes can partially be predicted. For example hydroxylation of the parent drug is in many cases the principal metabolic pathway. From a mass spectrometric point of view it results in an increase of 16 units in the mass spectrum. In the full-scan mode an extracted ion current profile can be used to screen for potential metabolites. In a second step a product ion spectrum is recorded for structural interpretation. Ideally, one would like to obtain relative molecular mass information and the corresponding product ion spectrum in the same LC-MS run. This information can be obtained by data dependant acquisition (DDA), as illustrated in Fig. 1.39. 

The metabolism of ticlopidine, 45, has been investigated by mass spectral analysis. The principal metabolic pathways can be proposed based on supporting mass spectrometry (MS) fragmentation patterns. Chlorotropylium ion 46 (mlz= 125) is the base peak in the product ion mass spectrum of ticlopidine <2004MI49>. 

Erythromycin distributes widely in the body with residue levels in tissues generally exceeding those in serum. Both hepatic and renal routes of elimination of erythromycin are significant and it undergoes enterohepatic circulation. Elimination of erythromycin in relatively high levels in the feces may follow its oral administration. As with almost all macrolides, the principal metabolic pathway of erythromycin is by A-desmethylation of the desosamine sugar (107). 

The principal metabolic pathway to mercapturic acids is presumably similar in humans and rodents. Because no data on kinetics or metabolic activation in humans are available, no quantitative comparison can be made. 

CONTENTS Acknowledgments, Margery G. Ord and Lloyd A. Stocken. Introduction. Biochemistry Before 1900. Early Metabolic Studies Energy Needs and the Composition of the Diet. Carbohydrate Utilization Glycolysis and Related Activities. Aspects of Carbohydrate Oxidation, Electron Transfer, and Oxidative Phosphorylation. Amino Acid Catabolism in Animals. The Utilization of Fatty Acids. The Impact of Isotopes 1925-1965. Biochemistry and the Cell. Concepts of protein Structure and Function. Chronological Summary of Main Events Up to ca. 1960. Principal Metabolic Pathways. Index. 

Figure 2 Principal metabolic pathways of inositol phospholipids.

A major consideration in using tolterodine is its pharmacokinetics, specifically its metabolism. The agent is predominantly eliminated by hepatic metabolism, and it exhibits genetic polymorphism. The principal metabolic pathway in extensive metabolizers involves oxidation of the parent drug by the CYP450 isoenzyme 2D6 to the active 5-hydroxymethyl metabolite (DDOl), followed by further oxidation and dealkylation. 

Heterocyclic disulfides are five- and six-carbon rings, which may also contain a cyclic thioether bond. The principal metabolic pathways are predicted to be disulfide reduction with ring opening to produce a dithiol and S-oxidation of the cyclic thioether. 

Figure 1 shows the principal metabolic pathways of B tP (a representative PAH) and the formation of some conjugates. In the interest of simplicity, further metabolic transformations, such as the P450 catalyzed oxidation of phenols to phenol-epoxides, conversion of phenols to phenol-dihydrodiols, all the enzymatic steps, and the stereochemistry of the metabolites are omitted. 

A summary of the principal metabolic pathways for the conversion of cholesterol to steroid hormones, intermediates, and metabolites together with porphyrin-inducing activities is presented in Fig. 5 [65]. The chick embryo liver cell tissue culture method was used for the determinations, and the inducing activities were related to the intensity of porphyrin fluorescence as observed in a fluorescence microscope. 

Oxygen is the ultimate electron acceptor in the principal metabolic pathways described in the previous chapters. In most aerobic organisms oxygen is reduced to water by cytochrome oxidase at rates that account... 

Figure 5.3. Principal metabolic pathways for brain monoamines. AD = aromatic L-amino acid decarboxylase, COMT = catechol-O-methyl-transferase, DH = dopamine-p-hydroxylase, MAO = monoamine oxidase, TH — tyrosine hydroxylase, TPH = tryptophan hydroxylase...

---