Drug-macromolecule conjugate

The transport mechanisms that operate in distribution and elimination processes of drugs, drug-carrier conjugates and pro-drugs include convective transport (for example, by blood flow), passive diffusion, facilitated diffusion and active transport by carrier proteins, and, in the case of macromolecules, endocytosis. The kinetics of the particular transport processes depend on the mechanism involved. For example, convective transport is governed by fluid flow and passive diffusion is governed by the concentration gradient, whereas facilitated diffusion, active transport and endocytosis obey saturable MichaeUs-Menten kinetics. 

Once a drug is conjugated to a macromolecule, it cannot enter the cell by simple diffusion but rather requires endocytosis, which could be enhanced in cancerous cells by overexpression of receptors. Therefore, to achieve cellular targeting, macromolecules require access to the interior of a cell through endocytosis, a process in which a portion of the plasma membrane invaginates to create a new intracellular vesicle (Fig. 12.6). Internalization via endocytosis can occur in one of two ways ... 

Devis, B.G. and Robinson, M.A. 2002. Drug delivery systems based on sugar—Macromolecule conjugates. Curr. Opin. Drug Discov. Dev. 5 279-288. 

Fig. 15 A schematic representation of an ideal macromolecule-drug conjugate. (From Ref. 206.)...

The methyl transferases (MTs) catalyze the methyl conjugation of a number of small molecules, such as drugs, hormones, and neurotransmitters, but they are also responsible for the methylation of such macromolecules as proteins, RNA, and DNA. A representative reaction of this type is shown in Figure 4.1. Most of the MTs use S-adenosyl-L-methionine (SAM) as the methyl donor, and this compound is now being used as a dietary supplement for the treatment of various conditions. Methylations typically occur at oxygen, nitrogen, or sulfur atoms on a molecule. For example, catechol-O-methyltransferase (COMT) is responsible for the biotransformation of catecholamine neurotransmitters such as dopamine and norepinephrine. A-methylation is a well established pathway for the metabolism of neurotransmitters, such as conversion of norepinephrine to epinephrine and methylation of nicotinamide and histamine. Possibly the most clinically relevant example of MT activity involves 5-methylation by the enzyme thiopurine me thy Itransf erase (TPMT). Patients who are low or lacking in TPMT (i.e., are polymorphic) are at... 

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