Biotransformation of Drugs

Many drugs undergo chemical modifi-cation in the body (biotransformation).Most frequently, this process entails aloss of biological activity and an in-crease in hydrophilicity (water solubil-ity), thereby promoting elimination viathe renal route. Since rapid drugelimination improves accuracy in titrat-ing the therapeutic concentration, drugsare often designed with built-in weaklinks. Ester bonds are such links, beingsubject to hydrolysis by the ubiquitousesterases. Hydrolytic cleavages, alongwith oxidations, reductions, alkylations,and dealkylations, constitute Phase I re-actions of drug metabolism. These reac-tions subsume all metabolic processesapt to alter drug molecules chemicallyand take place chiefly in the liver. InPhase II (synthetic) reactions, conju-gation products of either the drug itselfor its Phase I metabolites are formed, forinstance, with glucuronic or sulfuric ac-id.The special case of the endogenoustransmitter acetylcholine illustrateswell the high velocity of ester hydroly-sis. Acetylcholine is broken down at itssites of release and action by acetylchol-inesterase so rapidly as tonegate its therapeutic use. Hydrolysis ofother esters catalyzed by various este-rases is slower, though relatively fast incomparison with other biotransforma-tions. The local anesthetic, procaine, is acase in point; it exerts its action at thesite of application while being largelydevoid of undesirable effects at other lo-cations because it is inactivated by hy-drolysis during absorption from its siteof application.Ester hydrolysis does not invariablylead to inactive metabolites, as exempli-fied by acetylsalicylic acid. The cleavageproduct, salicylic acid, retains phar-macological activity. In certain cases,drugs are administered in the form ofesters in order to facilitate absorption(enalaprilenalaprilate; testosteroneundecanoatetestosterone) or to re-duce irritation of the gastrointestinal mucosa (erythromycin succinateerythromycin). In these cases, the esteritself is not active, but the cleavageproduct is. Thus, an inactive precursoror prodrug is applied, formation of theactive molecule occurring only after hy-drolysis in the blood.Some drugs possessing amidebonds, such as prilocaine, and of course,peptides, can be hydrolyzed by pepti-dases and inactivated in this manner.Peptidases are also of pharmacologicalinterest because they are responsiblefor the formation of highly reactivecleavage products andpotent mediators frombiologically inactive peptides.Peptidases exhibit some substrateselectivity and can be selectively inhib-ited, as exemplified by the formation ofangiotensin II, whose actions inter aliainclude vasoconstriction. Angiotensin IIis formed from angiotensin I by cleavageof the C-terminal dipeptide histidylleu-cine. Hydrolysis is catalyzed by “angio-tensin-converting enzyme”. Pep-tide analogues such as captopril block this enzyme. Angiotensin II is de-graded by angiotensinase A, which clipsoff the N-terminal asparagine residue.The product, angiotensin III, lacks vaso-constrictor activity.