Phase II Conjugations

Volume 400. Phase II Conjugation Enzymes and Transport Systems Edited by Helmut Sies and Lester Packer... 

Aromatic amines 4 are metabolised in vivo by cytochrome P450 mediated oxidation to phenolic and hydroxylamine derivatives 5 and 6. Phase II conjugation of the latter with PAPS or acyl transferase results in formation of the sulfuric or acetic acid esters 7. Nitrogen conjugation to give the A-acetyl analogues is also possible (Scheme l).54 65... 

Tab. 7.1 Division of enzymes into phase I and phase II. Phase I enzymes are normally oxidative and phase II conjugative.

One of the most important phase II conjugation reactions is that catalyzed by the glucuronyl transferases. A number of functional groups have the potential to be glu-curonidated as shown in Table 7.3, but phenol and carboxylic acid functions are of prime importance to the medicinal chemist. 

Similarly, quantitative structure-metabolism relationships (QSMR) have been studied [42]. QSAR tools, such as pattern recognition analysis, have been used to e. g. predict phase II conjugation of substituted benzoic acids in the rat [53]. 

Phase III reactions occur primarily in plants presumably because excretion of Phase II conjugates is Insignificant in plants. Phase III reactions are mechanisms whereby plants can reduce the effective concentration of xenobiotlc compounds in the cytoplasm. Thus, conjugation reactions provide mechanisms for the elimination of xenobiotlc compounds from sites of continuing metabolic activity in all organisms ( ) ... 

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

Phase II conjugative enzymes metabolize drugs by attaching (conjugating) a more polar molecule to the original drug molecule to increase water solubility,... 

The BZs are all metabolized in the liver via the hepatic cytochrome P450 (CYP) enzymes through one or both of the following pathways phase I oxidation and dealkylation, and/or phase II conjugation to glucuron-ides, sulfates, and acetylated compounds. Diazepam, chlordiazepoxide, and flurazepam all undergo both phase 1 and phase 11 metabolism. Lorazepam, lorme-tazepam, oxazepam, and temazepam are all metabolized by phase 11 alone and are better tolerated by patients with liver impairment. 

Mirtazapine has a half-life of 20 to 40 hours (319). Its elimination is principally dependent on CYP enzyme-mediated biotransformation as a necessary step. Three CYP enzymes—CYP 1A2, CYP 2D6, and CYP 3A3/4—mediate mirtazapine biotransformation to approximately an equal extent (320). Mirtazapine is also about 25% dependent on elimination by way of a phase II conjugation reaction with glucuronic acid. 

Precursor Ion Scan Precursor Fragment and Phase II Conjugates 146... 

---