Glucuronidation reactions

MgCl2 (1 and lOmM) enhanced the glucuronidation activity of HLMs toward estradiol, acetaminophen and morphine [22]. So it is beneficial to include MgCl2 in glucuronidation reactions. However, it may not be feasible to add MgCl2 to a high pH buffer system due to... 

Scheme 7. General glucuronidation reaction catalyzed by UDP-glucuronyl transferases.

Figure 6.31 GLucuronidation reactions (cataiysed by giucuronosyi transferases)...

Epperly AH, Cai Z, Depee SP et al. (2001) Pharmacokinetic analysis of a series of dianilinopyrimidine inhibitors of VEGFR2 tyrosine kinase correlation of the in vitro and in vivo metabolic stability of a specific glucuronidation reaction and the discovery of GW2286. Drug Metab Rev 33 243... 

In order to cover glucuronidation reactions in incubations in microsomal fractions several modifications have been applied in order to optimize conditions. These comprise longer incubation times than necessary for oxidative reactions by cytochrome P450s, and use of modifiers, both to overcome the latency in activity due to the diffusional barriers of the endoplasmatic reticulum (Coughtrie and Fisher 2003 Csala et al. 2004). Modifiers used are detergents or the pore-forming peptide alamethicin (Fisher 2000). Also disruption of cells by sonication is applied (Ethell 1998). 

The level and activity of specific enzymes involved in biotransformation can differ depending on the species, strain, age, and sex of the test animal. For example, cats cannot carry out glucuronidation reactions, newborn rats have relatively low cytochrome P450 activity, and male rats are more sensitive to carbon tetrachloride toxicity than female rats. These differences are important to consider when interpreting the results from toxicological studies. The observation that age, sex, and genetics can significantly influence biotransformation reactions in animals raises the question of whether these characteristics also affect the biotransformation capacity of humans. 

Figure 21 Examples of unusual glucuronidation reactions lamotrigine (quaternary ammonium glucuronide) and sulfinpyrazone (carbon-linked glucuronide). ...

A special class of acyl glucuronides are the carbamoyl glucuronides (reaction 4 in Fig. 

Hydroxylamines and hydroxylamides may also form 0-glucuronides (reaction 5, Fig. 

Figure 13.21. Major glucuronidation reactions involving phenols, alcohols, carboxylic acids, car-bamic acids, hydroxylamines and hydroxylamides, carboxamides, sulfonamides, various amines, thiols, dithiocarboxylic acids, and 1,3-dicarbonyl compounds.

Third in importance are the S-glucuro-nides formed from aliphatic and aromatic thiols (reaction 12 in Fig. 13.21) and from di-thiocarboxylic acids (reaction 13) such as di-ethyldithiocarbamic acid, a metabolite of dis-ulfiram. As for C-glucuronidation (reaction 14), this reaction has been seen in humans for 1,3-dicarbonyl drugs such as phenylbutazone and sulfinpyrazone (28) (Fig. 13.23). 

Fig. 31.29 Different metabolic pathways of p-amino-salicylic acid. Several conjugating enzymes are involved glycine TV-acyltransferases (reaction 1), UDP-glucuro-nosyltransferases (acyl-, ether-, A/-glucuronides, reactions 2, 4 and 6, respectively), sulfotransferases (reactions 3 and 5), A/-acetyltransferases (reaction 7).

Fig. 31.40 Active site and transition-state analogues (1) 7,7,7-triphenylheptanoic acid (2) w,(i),-triphenylalkyl-UDP (3) 3-5 -0-[[(2-decanoyl-3-phenylpropyloxycarbonyl)methyl]sulfonyl]uridine (DMSU). In insert, structure of a putative transition state analogue for the phenol glucuronidation reaction catalysed by UGT.

FIGURE 3.1 The glucuronidation reactions. Enzyme UDP glucuronosyltransferase (UGT or UDPGT) Cosubstrate uridene diphosphoglucuronic acid (UDPGA)-activated cosubstrate. 

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