Hydroxylated metabolites, obtained from

There is however a second phenomenon decisively influencing the optical purities of the alcohols formed in the course of Penicillium citrinum catalyzed reduction.The formed alcohols are metabolized again this metabolization proceeds enantioselectively. The preferentially formed (S)-enantiomer is preferentially metabolized. As shown in Table III the optical purity (% enantiomeric excess, e.e.) of nonan-2-ol decreases from 92% e.e.(S) to 12% e.e. (S). Heptan-2-ol is finally present mainly as (R)-enantiomer. The metabolization steps are currently under investigation one of the pathways is a hydroxy-lation leading to hydroxy ketones and diols. Figure 5 presents structures of hydroxylated metabolites obtained from nonan-2-one. 

Microbial transformations of four heteroyohimbine stereoisomers [ajmalicine (81a) tetrahydroalstonine (81b), isoajmalicine (81c), and akumigine (81d)] yielded mixtures of 10- and 11-hydroxylation products (786) (Scheme 21). Microorganisms known for their abilities to metabolize indole alkaloids, steroids, and antibiotics were intitially screened, and seven cultures were further used for preparative-scale incubations with alkaloid substrate. The microorganisms used and yields (by HPLC) of metabolites obtained from 81a-81d are shown in Table HI. 

In the case of deca-BDE, its suggested degradation process in mammals consists of a first reductive debromination where one, two or three bromine atoms can be replaced by hydrogen atoms followed by an oxidation to form hydroxylated metabolites, which are presumably formed from an intermediate epoxy [52]. This study detected traces of three nona-BDEs, which may be an indication of reductive debromination as a first step of degradation, and thirteen hydroxylated metabolites. Otherwise, the possibility of a deca-BDE oxidation as a first step to form the epoxy without an intermediate reductive debromination is also suggested [52]. The study conducted by Morck et al. [53] detected several hydroxylated products, from methoxy-hydroxy-pentabrominated to methoxy-hydroxy-heptabrominated compounds, which coincide with part of the metabolites obtained by Sandholm et al. [52]. In addition, both authors found that methoxy and hydroxy substituents are always on the same aromatic ring when both are present. Moreover,... 

Figure 6.5. Mass spectra of fa) di-hydroxylated metabolite (RT 28.6 min) and (b) a [M-10] metabolite of muraglitazar (RT 30.0min) in human fecal extracts following administration of muraglitazar. Upper panels obtained from MDF-simplified TIC (Fig. 6.4b) by combining scans over the peak and subtracting scans before and after the peak. Lower panels from unprocessed TIC (Fig. 6.4c) by combining and subtracting the same scan numbers in the respective upper panel (without MDF).

Phenytoin. Phenytoin (l s slowly absorbed from the small intestine. The rate, extent, and bioavailability vary because of the manufacturer s formulation process. Intramuscular injection tends to precipitate at the site of injection, resulting in erratic plasma levels these levels are significantly lower than those obtained by the oral route. Phenytoin is metabolized in the liver to inactive hydroxylated metabolites (see Fig. 6.3) (20). For a complete discussion, the reader is referred to the earlier edition of this chapter (8).The metabolism of phenytoin is capacity limited and shows satu-rability. Because the elimination of the p-hy-dro glucuronide metabolite is rate limited by its formation from phenytoin, measure-... 

Hydroxylation. The 2)8-hydroxylated derivative of cholic acid, 2, 3a,7a,12a-tetrahydroxy-5i8-cholanate, was characterized as a minor component of gastric contents of neonates with duodenal atresia [202], Identification was facilitated by the availability of the authentic compound, arapaimic acid, which was isolated from bile of Arapaima gigas (Chapter 10) and was synthesized [204], This tetrol is also a minor urinary metabolite of cholate in patients with intrahepatic cholestasis [123]. A polar bile acid formulated as a 2,3,6,7-tetrol obtained from urine of healthy newborn infants [199] apparently differs from an unidentified urinary tetrol from patients with cholestasis [164],... 

Hydroxylation. Urinary acids hydroxylated at position 6, especially 6a, include hyodeoxycholate, hyocholate, 3a,6 /, 12a-trihydroxy- and 3a,6a,7a,12 -tetrahy-droxy-5 -cholanates. Hyocholate, the major bile acid in urine, serum and duodenal fluid of a child with intrahepatic cholestasis [109], is a major urinary metabolite of chenodeoxycholate in patients with intrahepatic cholestasis, while 3a,6a,12a-trihy-droxy-5j3-cholanate is only a minor metabolite of deoxycholate [123]. The 3a,6a,7a,12a-tetrahydroxy acid, obtained from urine of patients with liver diseases [194] and from gastric contents of neonates with duodenal atresia [203] is another metabolite of cholic acid [123] several unidentified tetrols have yet to be char-... 

The metabolites appeared in the radiochromatograms of various matrices (plasma, urine, etc.) were analyzed by mass spectrometry. Comparison of the fragment ions of metabolites obtained by LC/MS/MS analysis to the ones from the parent compound provide structural information of the metabolite. Typical mass increases such as +16, +32, + 176, +80, +42, +14, —14, —60, and —2 indicate mono-hydroxylation, dihydroxylation, glucuronidation, sulfation, acetylation, methylation, demethylation, deacetylation, and dehydration, respectively. 

Early work in vitro on the sequence of reactions in the conversion of cholesterol into bile acids was carried out with mitochondrial preparations from rat and mouse liver (11). These preparations were found to catalyze predominantly reactions involving the oxidation of the side chain of C27-steroids. No evidence for the formation of 12a-hydroxylated metabolites was obtained. In 1963, Mendelsohn and Staple (12) reported the conversion of cholesterol into 5/ -cholestane-3a,7a-12a-triol in the presence of a 20,000 supernatant fluid of rat liver homogenate. This finding provided the first experimental evidence for the long surmised role of 5/ -cholestane-3a,7a,12a-triol as an intermediate in the conversion of cholesterol into cholic acid. Subsequent work with this enzyme preparation and subfractions of it has led to the elucidation of the sequences of reactions in the conversion of cholesterol into 5/ -cholestane-3a,7a,12a-triol (Fig. 1). 

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