Hydrolytic Reactions

1. Metabolic Changes of Drugs andRelated Organic CompoundsOrganic Pharmaceutical Chemistry I3rd Year Pharmacy2018-2019

2. Hydrolytic Reactions Because of the relative ease of hydrolysing the ester linkage, hydrolyis is the main pathway for drugs containing ester or amide linkages. Examples are; the hydrolysis of aspirin to…………………………...and cocaine to benzoylecogonine and …………............with he smaller, methyl group is hydrolysed preferentially. Exc: Draw the major and minor metabolites of hydrolysis of cocaine.

3. More Examples on Drug Hydrolysis Other examples of drug hydrolysis include that of retalin, diphenoxylate, clofibrate.

4. Prodrugs and Hydolysis

5. Amides Hydrolysis As compared to esters, amides are hydrolysed slowly. Exmaples of amides hydrolysis include; Procainamide, lidocaine, carbamazepine, succinamide and indomethacin. Exc: Compare the hydrolysis of prociane with that of procainamide.

6. More Hydrolytic Metabolism Hydrolysis of recombinant human peptide drugs and hormones at the N-or C-terminal amino acids by carboxypeptidase and aminopeptidases in blood and other tissues is well- recognized hydrolytic reaction. Examples of peptides or protein hormones undergoing hydrolysis include human insulin, growth hormone (GH) prolactin, parathyroid hormone (PTH), and atrial naturitic factor (ANF). More examples of hydrolysis include the hydrolysis of phosphate esters e.g. diethylstilbestrol diphosphate, sulphonylurears, cardiac glycosides, carbamate esters, and organophosphate compounds. Glucuronide and sulphate conjugates are also hydrolysed by glucurnidase and sulphatase enzymes respectively.

7. PHASE II OR CONJUGATION REACTIONS While phase I reactions do not always produce hydrophilic or pharmacologically inactive metabolites, the products of phase I reactions can be converted to more polar and soluble products. Many conjugative enzymes accomplish this objective by attaching a small, polar, and ionizable endogenous molecules, such as glucuronic acid, sulfate, glycine and glutamine, to the phase I metabolites or the parent xenobiotic.

8. PHASE II OR CONJUGATION REACTIONS As compared to phase I metabolites, phase II conjugated products are relatively more water soluble, readily excretable and biologically inactive and nontoxic Other phase II reactions, such as methylation and acetylation, do not generally increase water solubility but inactivate xenobiotics. GSH combine with chemically reactive compounds to prevent damage to DNA, RNA and proteins. Thus while, Phase I reactions are functionalization reactions, Phase II are detoxifying reactions.

9. PHASE II OR CONJUGATION REACTIONS Many endogenous compounds such as bilirubin, steroids, catecolamines, and histamine also undergo conjugation reactions and use the same coenzymes, although they appear to be mediated by more specific transferase enzymes. Other conjugative pathways are of minor importance including; conjugation with glycosides, phosphates and other amino acids and the conversion of cyanide to thiocyanate.

10. Glucuronic Acid Conjugation The reasons below demonstrate way glucuronic acid conjugation is the most common conjugative pathway in drug metabolism; • Readily available supply of D-glucuronic acid (derived from D-glucose). • Numerous functional groups can combine enzymetically with glucuronic acid. • Polar group of glucuranic acid (-COOH and 3 –OH) can be attached to xenobiotecs hence increasing thw water solubiloity of the product.

11. The Glucuronidation of Xenobiotic Numerous groups can undergo conjugative glucuronidation incuding; hydroxyl, carboxyl, amines, amides, sulphonamides, sulfhydryl and other carbon glucuronides. Attachment is normally to carbon atom 1 of the glucuronyl group. Phenolic and alcoholic groups are the most common groups undergoing glucurindation in drug meabolism. Morphine, acetaminophen, p-hydroxyphenytoin, tricloroethanol, chloramphenicol and propranolol. Examples for carboxyl groups include; naproxen and fenoprofen.

12. The Glucuronidation of Xenobiotics Several endogenous substrates are eliminated as glucoronide conjugates which as excreted primarily in the urine. However, as the molecular mass of the conjugate exceeds 300 Da, biliary excretion may become an important route of elimination through the bile and become subject to hydrolysis and reabsorption in the intestine.

13. The Sulphate Conjugation Sulphate conjugation occur mainly with phenols and occasionally with alcohols, aromatic amines and N-hydroxy compounds. The body uses a significant portion of the sulphate ions to to conjugate with numerous endogenous compounds such as steroids, heparin, chondroitin, catecolamines thyroxine. Suphate conjugation generally leads to water-soluble and inactive metabolites. However, some O-sulphate conjugates of some hydroxy compounds produce toxic reactive intermediates.

14. Sulphate Conjugation with Phenols Phenols undergoing sulphate conjugation include; α-methyldopa, salbutamol and terbutaline. The sulphate conjugation of N-hydroxyl compounds are of considerable toxicological concern because they can to reactive intermediates that are responsible for cellular toxicity. Examples are N-methyl-4-aminoazobenzene and 2-AAF O-sulphate conjugates are carcinogenic.

15. Sulphate Conjugation, the Phenacetin Example The same argument applies to the discontinued analgesic phenacetin for its hepatotoxicity and nephrotoxicity; N-hydroxlation, sulphate conjugation, removal of sulphate ion leaving an electrophile that can be stabilised by resonance and finally the attack of this electrophile by a nucleophile from DNA, RNA or proteins. Exc: Demonstrate the role of O-sulphate conjugation in the hepatotoxicity of phenacetin.