Synthetic Reactions

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Chapter: Essential pharmacology : Pharmacokinetics; Metabolism Excretion Of Drugs, Kinetics Of Elimination

These involve conjugation of the drug or its phase I metabolite with an endogenous substrate, generally derived from carbohydrate or amino acid, to form a polar highly ionized organic acid, which is easily excreted in urine or bile. Conjugation reactions have high energy requirement.


SYNTHETIC REACTIONS

 

These involve conjugation of the drug or its phase I metabolite with an endogenous substrate, generally derived from carbohydrate or amino acid, to form a polar highly ionized organic acid, which is easily excreted in urine or bile. Conjugation reactions have high energy requirement.

 

i)                   Glucuronide Conjugation

 

This is the most important synthetic reaction carriedout by a group of UDPglucuronosyl transferases (UGTs). Compounds with a hydroxyl or carboxylic acid group are easily conjugated with glucuronic acid which is derived from glucose. Examples are— chloramphenicol, aspirin, paracetamol, lorazepam, morphine, metronidazole. Not only drugs but endogenous substrates like bilirubin, steroidal hormones and thyroxine utilize this pathway. Glucuronidation increases the molecular weight of the drug which favours its excretion in bile. Drug glucuronides excreted in bile can be hydrolysed by bacteria in the gut—the liberated drug is reabsorbed and undergoes the same fate. This enterohepatic cycling of the drug prolongs its action, e.g. phenolphthalein, oral contraceptives.

 

ii)                Acetylation

 

Compounds having amino or hydrazine residues are conjugated with the help of acetyl coenzymeA, e.g. sulfonamides, isoniazid, PAS, hydralazine, clonazepam, procainamide. Multiple genes control the Nacetyl transferases (NATs), and rate of acetylation shows genetic polymorphism (slow and fast acetylators).

 

iii)             Methylation

 

The amines and phenols can be methylated; methionine and cysteine acting as methyl donors, e.g. adrenaline, histamine, nicotinic acid, methyldopa, captopril, mecarptopurine.

 

     iv) Sulfate Conjugation

 

The phenolic compounds and steroids are sulfated by sulfotransferases (SULTs), e.g. chloramphenicol, methyldopa, adrenal and sex steroids.

 

iv)              Glycine conjugation

 

Salicylates and other drugs having carboxylic acid group are conjugated with glycine, but this is not a major pathway of metabolism.

 

    vi) Glutathione conjugation

  

 Forming a mercapturate is normally a minor pathway. However, it serves to inactivate highly reactive quinone or epoxide intermediates formed during metabolism of certain drugs, e.g. paracetamol. When large amount of such intermediates are formed (in poisoning or after enzyme induction), glutathione supply falls short—toxic adducts are formed with tissue constituents tissue damage.

 

    vii) Ribonucleoside/nucleotide synthesis

 

This pathway is important for the activation of many purine and pyrimidine antimetabolites used in cancer chemotherapy.

 

Most drugs are metabolized by many pathways, simultaneously or sequentially as illustrated in Fig. 3.1. Rates of reaction by different pathways often vary considerably. A variety of metabolities (some more, some less) of a drug may be produced. Stereoisomers of a drug may be metabolized differently and at different rates, e.g. Swarfarin rapidly undergoes ring oxidation, while Rwarfarin is slowly degraded by sidechain reduction.

               


 

Only a few drugs are metabolized by enzymes of intermediary metabolism, e.g. alcohol by dehydrogenase, allopurinol by xanthine oxidase, succinylcholine and procaine by plasma cholinesterase, adrenaline by monoamine oxidase. Majority of drugs are acted on by relatively nonspecific enzymes which are directed to types of molecules rather than to specific drugs. The same enzyme can metabolize many drugs. The drug metabolising enzymes are divided into two types:


Microsomal Enzymes

 

These are located on smooth endoplasmic reticulum (a system of microtubules inside the cell), primarily in liver, also in kidney, intestinal mucosa and lungs. The monooxygenases, cytochrome P 450, glucuronyl transferase, etc. are microsomal enzymes.

 

They catalyse most of the oxidations, reductions, hydrolysis and glucuronide conjugation. Microsomal enzymes are inducible by drugs, diet and other agencies.

 

Nonmicrosomal Enzymes

 

These are present in the cytoplasm and mitochondria of hepatic cells as well as in other tissues including plasma. The flavoprotein oxidases, esterases, amidases and conjugases are nonmicrosomal. Reactions catalysed are:

 

Some oxidations and reductions, many hydrolytic reactions and all conjugations except glucuronidation.

 

The nonmicrosomal enzymes are not inducible but many show genetic polymorphism (acetyl transferase, pseudocholinesterase).

 

Both microsomal and nonmicrosomal enzymes are deficient in the newborn, especially premature, making them more susceptible to many drugs, e.g. chloramphenicol, opioids. This deficit is made up in first few months, more quickly in case of oxidation and other phase I reactions than in case of glucuronide and other conjugations taking 3 or more months.

 

The amount and kind of drug metabolizing enzymes is controlled genetically and is also altered by environmental factors. Thus, marked interspecies and interindividual differences are seen, e.g. cats are deficient in glucuronyl transferase while dogs are deficient in acetyl transferase. Upto 6fold difference in the rate of metabolism of a drug among normal human adults may be observed. This is one of the major causes of individual variation in drug response.

 

Hofmann Elimination

 

This refers to inactivation of the drug in the body fluids by spontaneous molecular rearrangement without the agency of any enzyme, e.g. atracurium. 

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