Metabolites, plasma

Parkhurst et al. [79] described a high performance liquid chromatographic method for the simultaneous determination of primaquine and its metabolites from plasma and urine samples, utilizing acetonitrile deproteinization, and direct injection onto a cyano column. Levels of 100 ng/mL per 20 pL injection could be quantitated. Preliminary pharmacokinetic analysis is reported for two human subjects after oral doses of 60 90 mg primaquine diphosphate. Two apparent plasma metabolites and two possible urinary metabolites are also reported. 

Mihaly et al. [128] identified the carboxylic acid derivative of primaquine as a major plasma metabolite. After oral administration of 45 mg of primaquine to healthy volunteers, absorption of the drug was rapid, with peak primaquine levels of 153.3 ng/mL at 3 h, followed by an elimination half-life of 7.1 h, systemic clearance of 21.1 L/h, volume of distribution of 205 L and cumulative urinary excretion of 1.3% of the dose. Primaquine was converted rapidly to the carboxylic acid metabolic, which achieved peak levels of 1427 ng/mL at 7 h. 

Rivory LP, Riou JF, Haaz MC et al. Identification and properties of a major plasma metabolite of irinotecan (CPT-11) isolated from the plasma of patients. Cancer Res 1996 56 3689-3694. 

The main human plasma metabolite of chlormezanone (5.75), a muscle relaxant, was found to be the ring-opened compound 5.76. Since hydrolysis... 

Metabonomics has changed the way data are analyzed. Instead of the single biomarker concept, the goal is to simultaneously measure the entire range of plasma metabolites to see changes in the patterns of the biomarkers. This requires both analytical platforms that can assess the broad range of metabolites in an individual and the knowledge of metabolism that is necessary to interpret the analytical data. 

Murphey LJ, Hachey DL, Vaughan DE, Brown NJ, Morrow JD. 2001. Quantification of BKl-5, the stable bradykinin plasma metabolite in humans, by a highly accurate liquid chromatographic tandem mass spectrometric assay. Anal Biochem 292 87. 

Another recent innovation is the QTrap mass spectrometer. The QTrap MS system combines the capabilities of a triple quadrupole mass spectrometer and a linear ion trap mass spectrometer into one MS system. Initially, the QTrap MS was used primarily as a tool for metabolite identification studies [34, 35, 38]. As reported by Li et al. [138], the QTrap MS can also be used as an excellent system for the quantitative analysis of discovery PK samples. The advantage of the QTrap MS system for quantitative analysis is that it can be used to look for plasma metabolites of the NCE and provide an easy way to monitor them while providing the quantitative data on the NCE. 

Refers to cotinine, the primary plasma metabolite of nicotine. 

O. 69 LVh/kg renal and biliary clearance of unchanged drug each contribute approximately 5%. About 30% of the dose is excreted in the feces 53% of the oral dose is excreted in the urine, primarily as metabolites. Of the five metabolites that have been identified, 25-0-desacetyl and 31-hydroxy are the most predominant, and show a plasma metabolite parent ADC ratio of 0.1 and 0.07, respectively. The 25-0-desacetyl metabolite has an activity equal to the parent drug and contributes less than or equal to 10% to the total antimicrobial activity. 

Published human data are summarized in Table 6.3. Although the maximum concentration achieved transiently varies to some extent with PPT subclass and matrix in which it is consumed, it is unlikely that plasma metabolite concentrations will routinely exceed 10 pMin total, and 1 lM for total aglycones. The reported Tjnax values range from 1 to 2.5 h for substances absorbed in the duodenum,up to 5 to 12 h when microbial metabolism is a prerequisite.Published elimination half-lives are very variable, ranging from as low as 1 to values in excess of 20 i57,i5s,i6o values may be artifacts of... 

Koga, T. and Meydani, M., Effect of plasma metabolites of (+)-catechin and quercetin on monocyte adhesion to human aortic endothelial cells. Am. J. Clin. Nutr., 73, 941, 2001. 

Pharmacokinetic data have demonstrated very good absorption of the orally administered oxfendazole to cattle and sheep. After administration of the drug, the plasma metabolite pool is composed of oxfendazole, fenbendazole sulfone. 

Inflammation is now recognized as a key process in atherogenesis [Libby, 2002]. The potential for dietary flavonoids to inhibit inflammatory activities is of particular interest. A potential anti-inflammatory feature of the flavonoids is the ability to inhibit the biosynthesis of eicosanoids. Selected phenolic acids and some flavonoids have been shown to inhibit both cyclooxygenase (COX) and 5-lipoxygenase (5-LO) pathways [Nijveldt et al., 2001 Takano-Ishikawa et al., 2006], Epicatechin and related flavonoids have been shown to inhibit the synthesis of pro-inflammatory cytokines in vitro [Sanbongi et al., 1997], and plasma metabolites of catechin and quercetin inhibit the adhesion of monocytes to cultured endothelial cells [Koga and Meydani, 2001]. Silymarin has been shown to inhibit the production of inflammatory cytokines, such as interleukin-1, interferon-, and tumor necrosis factor-a (TNFa), from macrophages and T-cells [Matsuda et al., 2005], Some flavonoids can inhibit neutrophil... 

Day AJ, Mellon F, Barron D, Sarrazin G, Morgan MRA, Williamson G. 2001. Human metabolism of dietary flavonoids identification of plasma metabolites of quercetin. Free Radic Res 35 941-952. 

Animals Source Administration Dose mg/kg Blood or Seram or Plasma Metabolites (Concentration) Urinary excretion % Metabolites Time (h) Reference... 

F. Lokiec, J.P. Armand, and J. Robert. 1997. Pharmacokinetic interrelationships ofirinotecan (CPT-11) and its three major plasma metabolites in patients enrolled in phase I/II trials. Clin. Cancer Res. 3 1261-1266. 

M27. Morand, C., Crespy, V., Manach, C., Besson, C., Demigne, C., and Remesy, C., Plasma metabolites of quercetin and their antioxidant properties. Am. J. Physiol. 275, R212-R219 (1998). 

Chemical metabolism can be described qualitatively or quantitatively. Many scientists can make qualitative predictions of the likely excretion products or blood plasma metabolites in mammals, or a particular animal including man, based on accumulated knowledge and experience. Such knowledge, in its raw form, generally consists of structure-metabolism relationships that are frequently expressible as qualitative structure-based rules that may be encoded into computer-based expert systems (see Chapter 9 for a full definition). Examples of such systems, in their more fully developed commercial forms, are discussed toward the end of this chapter. 

Schweer H, Meese CO, Watzer B, Seyberth HW (1994) Determination of prostaglandin El and its main plasma metabolites 15-keto-prostaglandin EO and prostaglandin EO by gas chromatography/negative ion chemical ionization triplestage quadrupole mass spectrometry. Biol Mass Spectrom 23 165-170... 

Disposition in the Body. Slowly and incompletely absorbed after oral administration distributed to the tissues where it is strongly bound. Metabolised by V-dealkylation to monodesethylamiodarone which is the major plasma metabolite during chronic dosing. High concentrations of amiodarone and monodesethylamiodarone are found in the liver, lungs, and adipose tissue. Enterohepatic circulation may occur. Only a small amount is excreted in the urine as unchanged drug. 

Disposition in the Body. Readily absorbed after oral administration. It undergoes first-pass acetylation, the extent of which is genetically determined bioavailability 30 to 35% in slow acetylators, 10 to 16% in rapid acetylators. The major metabolites are 3-methyl-l,2,4-triazolo[3,4-a]phthalazine (MTP—the acetylation product) hydralazine pyruvic acid hydrazone (HPH) which is the major plasma metabolite 4-(2-acetylhydra-zino)phthalazin-l-one (A-AcHPZ) which is the major urinary metabolite 3-hydroxymethyl-1,2,4-triazolo[3,4-a]phthalazine (3-OHMTP). About 65% of a dose is excreted in the urine in 24 hours. In rapid acetylators, about 30% is excreted as A-AcHPZ and 10 to 30% as conjugated 3-OHMTP in slow acetylators, about 15 to 20% is excreted as A-AcHPZ and up to 10% as conjugated 3-OHMTP. Other metabolites include phthalazin-1-one (PZ), 1,2,4-triazolo[3,4-fl]phthalazine (TP), 9-hydroxy-MTP, phthalazine, tetrazolo[5,l-a]phthalazine, and hydrazones of hydralazine formed with acetone and a-ketoglutaric acid. About 10% of a dose is eliminated in the faeces. 

Disposition in the Body. Readily absorbed after oral administration. It is extensively metabolised by oxidation to carboxyprimaquine which is the major plasma metabolite. Other reactions which may occur are demethylation and oxidation to the 5,6-diol, which is then converted to an active quinone, V-dealkylation to 8-amino-6-methoxyquinoline, and iV-acetyla-tion. Less than 5% of a dose is excreted in the urine unchanged in 24 hours. 

High Pressure Liquid Chromatography. In monkey plasma metabolites of thymoxamine, detection limits 2 ng for desacetylthymoxamine and 4 ng for desmethyldesacetylthymoxamine, fluorescence detection—A. E. Geahchan and P. L. Chambon, Analyt. Chem., 1980, 52, 999-1001. 

FIGURE 4.4 Changes in plasma metabolite and hormone levels with exercise. The human subjects were at n st at time zero. Exercise was coitiinucd for 250 min, and concentrations of plasma glucose (O), glucagon (A), and insulin ) were measured at the indicated times. (Redrawn with permission from Felig and Wahren, J975.)... 

The striking connection between premature cardiovascular disease and high levels of homocysteine, in homocysteinuria, prompted a look at possible relationships between cardiovascular disease and moderate levels of homocysteine. This close look has included genetic analysis, the biochemical analysis of plasma metabolite levels, and epidemiological studies. Clearly, exploration by researchers into the effects of moderate elevations of homocysteine has been a multidisciplinary effort. The studies have taken these forms ... 

The antiarrhythmic agent quinidine is metabolized by allylic hydroxylation to 3-hydroxyquinidinc. the principal plasma metabolite found in humans. This metabolite shows significant antiarrhythmic activity in animals and po.s-sibly in humans. -"... 

When chiral ketones are reduced, they yield two possible diastereomeric or epimcric alcohols. For example, the IRK +) enantiomer of the oral anticoagulant warfarin undergoes extensive reduction of its side chain keto group to generate the (R.S)( +) alcohol as the major plasma metabolite in humans. - Small amounts of the ( ./ )(+) diastereo-nier also ate formed. In contrast, the (5)(-) enantiomer undergoes little ketone reduction and is primarily 7-hydroxy-bied (ie.. aromatic hydroxylatton) in humans. 

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