Biotransformation of Drugs

Many drugs undergo chemical modification in thebody(biotransformation). Most often this process entails a loss of biological activity and an increase in hydrophilicity (water solubility), thereby promoting elimination via the renal route (p.40). Since rapid drug elimination improves accuracy in titrating the therapeutic concentration, drugs are often designed with built-in weak links. Ester bonds are such links, being subject to hydrolysis by the ubiquitous esterases.

Hydrolytic cleavages, along with oxidations, reductions, alkylations, and dealkylations, constitute phase I reactions of drug metabolism. These reactionssubsume all metabolic processes apt to alter drug molecules chemically and take place chiefly in the liver. In phase II (synthetic) reactions, conjugation products of either the drug itself or its phase I metabolites are formed, for instance, with glucuronic or sulfuric acid

The special case of the endogenous transmitter acetylcholine illustrates well the high velocity of ester hydrolysis. Acetylcholine is broken down so rapidly at its sites of release and action by acetylcholinesterase (p.106) as to negate its therapeutic use. Hydrolysis of other esters catalyzed by various esterases is slower; though relatively fast in comparison with other biotransformations. The local anesthetic procaine is a case in point; it exerts its action at the site of application while being largely devoid of undesirable effects at other locations because it is inactivated by hydrolysis during absorption from the site of application.

Ester hydrolysis does not invariably lead to inactive metabolites, as exemplified by acetylsalicylic acid. The cleavage product, salicylic acid, retains pharmacological activity. In certain cases, drugs are administered in the form of esters in order to facilitate uptake into the body (enalapril–enalaprilat, p.128; testosterone decanoate–testosterone, p.248) or to reduce irritation of the gastric or

intestinal mucosa (acetylsalicylic acid–sali- cylic acid; erythromycin succinate–erythro- mycin). In these cases the ester itself is not active but its hydrolytic product is. Thus, an inactive precursor or prodrug is administered and formation of the active molecule occurs only after hydrolysis in the blood.

Some drugs possessing amide bonds, such as prilocaine and of course peptides, can be hydrolyzed by peptidases and inactivated in this manner. Peptidases are also of pharmacological interest because they are responsible for the formation of highlyreactive cleavage products (fibrin, p.150) and potent mediators (angiotensin II, p.128; bradykinin, enkephalin, p.208) from biologically inactive peptides.

Peptidases exhibit some substrate selectivity and can be selectively inhibited, as exemplified by the formation of angiotensin II, whose actions inter alia include vasoconstriction. Angiotensin II is formed from angiotensin I by cleavage of the C-terminal dipeptide histidylleucine. Hydrolysis is catalyzed by “angiotensin-converting enzyme” (ACE). Peptide analogues such as captopril (p.128) block this enzyme. Angiotensin II is degraded byangiotensinase A, which cleaves off the N-terminal asparagine residue. The product angiotensin III lacks vasoconstrictor activity.

Oxidation reactions can be divided into two kinds: those in which oxygen is incorporated into the drug molecule, and those in which primary oxidation causes part of the molecule to be lost. The former include hydroxylations, epoxidations, and sulfoxidations. Hydroxylations may involve alkyl substituents (e.g., pentobarbital) or aromatic ring systems (e.g., propranolol). In both cases, products are formed that are conjugated to an organic acid residue, e.g., glucuronic acid, in a subsequent phase II reaction.

Hydroxylation may also take place at nitrogens, resulting in hydroxylamines (e.g., acetaminophen). Benzene, polycyclic aromatic compounds, (e.g., benzopyrene), and unsaturated cyclic carbohydrates can be converted by monooxygenases to epoxides, highly reactive electrophiles that are hepatotoxic and possibly carcinogenic.

The second type of oxidative biotransformation comprises dealkylations. In the case of primary or secondary amines, dealkylation of an alkyl group starts at the carbon adjacent to the nitrogen; in the case of tertiary amines, with hydroxylation of the nitrogen (e.g., lidocaine). The intermediary products are labile and break up into the dealkylated amine and aldehyde of the alkyl group removed. O-dealkylation and S-dear- ylation proceed via an analogousmechanism (e.g., phenacetin and azathioprine, respectively).

Oxidative deamination basically resembles the dealkylation of tertiary amines, beginning with the formation of a hydroxylamine that then decomposes into ammonia and the corresponding aldehyde. The latter is partly reduced to an alcohol and partly oxidized to a carboxylic acid.

Reduction reactions may occur at oxygen or nitrogen atoms. Keto oxygens are converted into a hydroxyl group, as in the reduction of the prodrugs cortisone and prednisone to the active glucocorticoids cortisol and prednisolone, respectively. N-reductions occur in azo or nitro compounds (e.g., nitrazepam). Nitro groups can be reduced to amine groupsvia nitroso and hydroxylamino intermediates. Likewise, dehalogenation is a reductive process involving a carbon atom (e.g., halothane, p.216).

Methylations are catalyzed by a family of relatively specific methyltransferases involving the transfer of methyl groups to hydroxyl groups (O-methylation as in norepinephrine [noradrenaline]) or to amino groups (N- methylation of norepinephrine, histamine, or serotonin).

In thio compounds, desulfuration results from substitution of sulfur by oxygen (e.g., parathion). This example again illustrates that biotransformation is not always to be equated with bioinactivation. Thus, paraoxon (E600) formed in the organism from parathion (E605) is the actual active agent (bioactivation, “toxification”, p.106)