Hydrolysis of Esters and Amides
The metabolism of ester and amide linkages in many drugs is catalyzed by hydrolytic enzymes present in various tissues and in plasma. The metabolic products formed (car-boxylic acids, alcohols, phenols, and amines) generally are polar and functionally more susceptible to conjugation and excretion than the parent ester or amide drugs. The enzymes carrying out ester hydrolysis include several nonspecific esterases found in the liver, kidney, and intestine as well as the pseudocholinesterases present in plasma.336,337 Amide hydrolysis appears to be mediated by liver microsomal amidases, esterases, and deacylases.337
Hydrolysis is a major biotransformation pathway for drugs containing an ester functionality. This is because of the relative ease of hydrolyzing the ester linkage. A classic example of ester hydrolysis is the metabolic conversion of aspirin (acetylsalicylic acid) to salicylic acid.338 Of the two ester moieties present in cocaine, it appears that, in general, the methyl group is hydrolyzed preferentially to yield benzoylecgonine as the major human urinary metabolite.339 The hydrolysis of cocaine to methyl ecgonine, however, also occurs in plasma and, to a minor extent, blood.340,341 Methylphenidate (Ritalin) is biotransformed rapidly by hydrolysis to yield ritalinic acid as the major urinary metabolite in humans.342 Often, ester hydrolysis of the parent drug leads to pharmacologically active metabolites. For example, hydrolysis of diphenoxylate in humans leads to diphenoxylic acid (difenoxin), which is, apparently, 5 times more potent an antidiarrheal agent than the parent ester.343 The rapid metabolism of clofibrate
Many parent drugs have been chemically modified or de-rivatized to generate so-called prodrugs to overcome some undesirable property (e.g., bitter taste, poor absorption, poor solubility, irritation at site of injection). The rationale behind the prodrug concept was to develop an agent that, once inside the biological system, would be biotransformed to the active parent drug.18 The presence of esterases in many tissues and plasma makes ester derivatives logical prodrug candidates, because hydrolysis would cause the ester prodrug to revert to the parent compound. Accordingly, antibiotics such as chloramphenicol and clindamycin have been derivatized as their palmitate esters to minimize their bitter taste and to improve their palatability in pediatric liquid suspensions.346,347 After oral administration, intestinal esterases and lipases hydrolyze the palmitate esters to the free antibiotics. To improve the poor oral absorption of car-benicillin, a lipophilic indanyl ester has been formulated (Geocillin).348 Once orally absorbed, the ester is hydrolyzed rapidly to the parent drug. A final example involves deriva-tization of prednisolone to its C-21 hemisuccinate sodium salt. This water-soluble derivative is extremely useful for parenteral administration and is metabolized to the parent steroid drug by plasma and tissue esterases.349
Amides are hydrolyzed slowly in comparison to es-ters.337 Consequently, hydrolysis of the amide bond of procainamide is relatively slow compared with hydrolysis of the ester linkage in procaine.336,350 Drugs in which amide cleavage has been reported to occur, to some extent, include lidocaine,351 carbamazepine,87 indomethacin,251,252 and prazosin (Minipress).253,254 Amide linkages present in barbiturates (e.g., hexobarbital)352,353 as well as in hydantoins (e.g., 5-phenylhydantoin)354,355 and succinimides (phensux-imide)354,355 are also susceptible to hydrolysis.
Hydrolysis of recombinant human peptide drugs and hormones at the N- or C-terminal amino acids by carboxypep-tidase and aminopeptidase and proteases in blood and other
tissues is a well-recognized hydrolytic reaction.356,357 Examples of peptides or protein hormones undergoing hydrolysis include human insulin, growth hormone (GH), prolactin, parathyroid hormone (PTH), and atrial natriuretic factor (ANF).358
In addition to hydrolysis of amides and esters, hydrolytic cleavage of other moieties occurs to a minor extent in drug metabolism,8 including the hydrolysis of phosphate esters (e.g., diethylstilbestrol diphosphate), sulfonylureas, cardiac glycosides, carbamate esters, and organophosphate compounds. Glucuronide and sulfate conjugates also can undergo hydrolytic cleavage by jS-glucuronidase and sulfatase enzymes. These hydrolytic reactions are discussed in the following section. Finally, the hydration or hydrolytic cleavage of epoxides and arene oxides by epoxide hydrase is considered a hydrolytic reaction.
Throughout this chapter, the metabolism of produgs to an active form is presented. However, in the cases presented earlier, there was a chemical functional group that was subject to phase I metabolism to release the active drug molecule.
The metabolic reactions included oxidative activation, reductive activation, hydrolytic activation, etc. One reaction that is of particular interest involves chemical activation as seen with the proton pump inhibitors, which are clinically used to treat gastric ulceration. When administered to a patient, the drug is dosed orally, allowing for systemic distribution. When the proton pump inhibitor arrives at an acidic region of the body, such as the parietal cells of the stomach, chemical activation occurs. The highly acidic environment in and around the parietal cell allows for protonation of nitrogen on the benzimidazole ring, followed by attachment of the pyri-dine nitrogen. Ring opening of the intermediate then yields the sulfenic acid that subsequently cyclizes with the loss of water. This intermediate is highly susceptible to nucleophilic attack by the SH moieties of the cysteine residues associated with proteins, including the proton pump of the parietal cells. This pump is responsible for exchange of K+ with H+ from parietal cell into gastric lumen, and through this inhibition, there is regulation of the acidic environment of stomach.
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