Chemical Pathways of Drug Biotransformation

CHEMICAL PATHWAYS OF DRUG BIOTRANSFORMATION

R.T.Williams, the leading pioneer in drug biotransformation research, divided the pathways of drug metabolism reactions into two general categories—

^·            Phase I reactions, and

^·            Phase II reactions.

Phase I Reactions

These reactions generally precede phase II reactions and include oxidative, reductive and hydrolytic reactions. By way of these reactions, a polar functional group is either introduced or unmasked if already present on the otherwise lipid soluble substrate, e.g. -OH, -COOH, - NH₂ and -SH. Thus, phase I reactions are also called as functionalisation reactions.

These transformations are also called as asynthetic reactions, opposite to the synthetic phase II reactions. The resulting product of phase I reaction is susceptible to phase II reactions.

Phase II Reactions

These reactions generally involve covalent attachment of small polar endogenous molecules such as glucuronic acid, sulphate, glycine, etc. to either unchanged drugs or phase I products having suitable functional groups viz. -OH, -COOH, -NH₂ and -SH and form highly water-soluble conjugates which are readily excretable by the kidneys (or bile). Thus, these reactions are called as conjugation reactions. Since the outcome of such processes are generally products with increased molecular size (and altered physicochemical properties), they are also called as synthetic reactions. Quite often, a phase I reaction may not yield a metabolite that is sufficiently hydrophilic or pharmacologically inert but conjugation reactions generally result in products with total loss of pharmacological activity and high polarity. Hence, phase II reactions are better known as true detoxification reactions. Since these reactions generally involve transfer of moieties to the substrate to be conjugated, the enzymes responsible are called as transferases.

The biotransformation of drug metabolites, particularly the glutathione conjugates which are excreted via bile in the gut, by the intestinal microflora, is considered by few researchers as phase III reactions.

Quite commonly, the biotransformation reactions proceed sequentially and the combination of several phase I and phase II reactions yield a range of metabolites (Fig. 5.2).

Fig. 5.2. Sequence of phase I and phase II reactions yielding a range of products The various phase I and phase II reactions are listed in Table 5.2

TABLE 5.2. Chemical Pathways of Drug Biotransformation — (M) and (N) Indicate Reactions Catalysed by Microsomal and Non-microsomal Enzymes