Drug Metabolism in Drug Design and Development Basic Concepts and Practice

3 Conjugative Metabolism of Drugs

RORYREMMEL,SWATINAGAR ANDUPENDRAARGIKAR

3.1 UDP-Glucuronosyltransferases

Glucuronidation is the addition (conjugation) of glucuronic acid to various
functional groups. Compounds may be glucuronidated directly or after
oxidative metabolism (Phase II metabolism). Reactions can occur on alcohols
(ROH), phenols (Ar–OH), amines (RNH 2 ), tertiary and heterocylic amines
(RNR^0 R^00 ), amides (R–CO–NH 2 ) thiols (RSH), and acidic carbon atoms
(Fig. 3.1). Addition of glucuronic acid results in conjugates that are

1. more polar


2. are ionized at physiologic pH (pKa4)


3. have an increase molecular weight (+176).
   These features facilitate excretion of glucuronides via the kidney either
   by glomerular filtration or by active secretion or both. In addition, glucuronides
   are commonly excreted by the liver via the bile into the small intestine.
   Glucuronides are too polar to diffuse through cell membranes and therefore
   specific transporters are necessary for their movement across membranes.
   Monoglucuronides are generally considered to be final metabolites,
   although there is recent evidence with some of the nonsteroidal anti-
   inflammatory agents, that glucuronides may be substrates for CYP2C9
   oxidation. Diglucuronides of bilirubin, some steroids, and di-OH chrysene
   (a polycyclic aromatic hydrocarbon) have also been observed.

Drug Metabolism in Drug Design and Development, Edited by Donglu Zhang, Mingshe Zhu
and W. Griffith Humphreys
Copyright#2008 John Wiley & Sons, Inc.

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