Conjugate metabolites phase

Keywords Microorganisms, Fungi, Hydroxylation, Screening, Biotransformation, Metabolites, Phase 1, Phase 11, Glyco conjugates. Toxicology, Pharmacology. 

Fig. 3. Phase I adds a small reactive portion to the drug molecule, and Phase II conjugates the Phase I metabolite to an...

The water-soluble metabolites of sedative-hypnotics, mostly formed via the conjugation of phase I metabolites, are excreted mainly via the kidney. In most cases, changes in renal function do not have a marked effect on the elimination of parent drugs. Phenobarbital is excreted unchanged in the urine to a certain extent (20-30% in humans), and its elimination rate can be increased significantly by alkalinization of the urine. This is partly due to increased ionization at alkaline pH, since phenobarbital is a weak acid with a pKa of 7.4. 

Conjugated metabolites delivered to the liver are metabolized by hepatic phase II enzymes. The latter were reported to convert conjugated quercetin metabolites to a wide variety of their conjugates with and without deconjugation [Day et al., 1998 van de Woude et al., 2004]. Conjugated metabolites are released into the circulation after secondary metabolism in the liver. Considerable amounts of conjugated metabolites also simultaneously enter bile and return to the intestinal tract together with bile components. This enterohepatic circulation should be considered if the overall bioavailability of flavonols is discussed. 

Figure 2.22. Outline of hepatic dmg metabolism and its role in drag elimination. I, II Phase I and phase II reactions. Some drags skip the phase I reaction and are directly conjugated. Metabolites may be either released into the blood stream and eliminated by the kidneys, or they may be secreted into the bile. In the latter case, deconjugation may occur in the intestine (largely due to bacterial enzymes), and the drags released may undergo entero-hepatic cycling .

The metabolites are generally identified as metabolites of Phase I oxidation or Phase II conjugation. If Phase I oxidation is concluded as the major pathway for the oxidative metabolism of the drug, a second study will be performed to evaluate which of the several oxidative pathways are involved. Phase II conjugation pathways can be generally recognized by the identity of the metabolite, and subsequent experiments to further identify the pathways may not be necessary. For instance, if the metabolite is a glucuronide, UGT can be identified as the enzyme involved. 

PAHS are readily absorbed via the gastrointestinal tract and then metabolically transformed to more reactive forms. These toxicants are typically converted into more reactive metabolites through phase I biotransformations, and then converted into more readily excretable conjugates via phase II processes. 

There are several different types of hydrolytic reactions and enzymes car-boxylesterases, epoxide hydrolases, drug conjugate cleavage enzymes (glucuronidase, sulfatase, or phosphatase), and peptidases. The process of (3-oxidation described previously could also be considered a cleavage reaction. These reactions generally produce a metabolite that is more polar and susceptible to conjugation by Phase II enzymes. 

Concentrations of aloe-emodin, rhein, an unknown metabolite, and their conjugated metabolites were determined in plasma, urine, feces, liver, and kidney using TLC (Lang, 1993). Thin layer chromatograms were prepared on silica gel, and mobile phases used included an ethyl acetate-methanol-water (100/... 

Metabolism of mebendazole occurs primarily by reduction of the 5-carbonyl to a secondary alcohol, which greatly increases the water solubility of this compound. An additional Phase I metabolite resulting from carbamate hydrolysis has been reported as well. Both the secondary alcohol and the amine are readily conjugated (a Phase II metabolism). Evidence would suggest that the anthelmintic activity of mebendazole resides in the parent drug and none of the metabolites. 

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