Non-Synthetic Reactions

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

This reaction involves addition of oxygen/negatively charged radical or removal of hydrogen/positively charged radical. Oxidations are the most important drug metabolizing reactions. Various oxidation reactions are: hydroxylation; oxygenation at C, N or S atoms; N or Odealkylation, oxidative deamination, etc.


NON-SYNTHETIC REACTIONS

 

i) Oxidation

 

This reaction involves addition of oxygen/negatively charged radical or removal of hydrogen/positively charged radical. Oxidations are the most important drug metabolizing reactions. Various oxidation reactions are: hydroxylation; oxygenation at C, N or S atoms; N or Odealkylation, oxidative deamination, etc.

 

In many cases the initial insertion of oxygen atom into the drug molecule produces short lived highly reactive quinone/epoxide/superoxide intermediates which then convert to more stable compounds.

 

Oxidative reactions are mostly carried out by a group of monooxygenases in the liver, which in the final step involve a cytochrome P450 haemoprotein, NADPH, cytochrome P450 reductase and molecular O2. More than 100 cytochrome P450 isoenzymes differing in their affinity for various substrates (drugs), have been identified.

 

Depending upon the extent of amino acid sequence homology, the cytochrome P450 (CYP) isoenzymes are grouped into families designated by numerals (1, 2, 3.....), each having several subfamilies designated by capital letters (A, B, C.....), while individual isoenzymes are again alloted numerals (1, 2, 3....). In human beings, only a few members of three isoenzyme families (CYP 1, 2 and 3) carryout metabolism of most of the drugs, and many drugs such as tolbutamide, barbiturates, nifedipine are substrates for  more than one isoform. The CYP isoenzymes important in man are:

 

CYP3A4/5 Carryout biotransformation of largest number (nearly 50%) of drugs. In addition to liver, these isoforms are expressed in intestine (responsible for first pass metabolism at this site) and kidney as well. Inhibition of this isoenzyme by erythromycin, clarithromycin, ketoconazole, itraconazole is responsible for the important drug interaction with terfenadine, astemizole and cisapride (see p. 158) which are its substrates. Losartan, nifedipine and cyclosporine are also metabolized by CYP3A4/5. Verapamil, diltiazem, ritonavir and a constituent of grape fruit juice are other important inhibitors, while rifampicin, barbiturates and other anticonvulsants are the important inducers.

 

CYP2D6 This is the next most important CYP isoform which metabolizes nearly 20% drugs including tricyclic antidepressants, selective serotonin reuptake inhibitors, many neuroleptics, antiarrhythmics, βblockers and opiates. Inhibition of this enzyme by quinidine results in failure of conversion of codeine to morphine analgesic effect of codeine is lost. Human subjects can be grouped into ‘extensive’ or ‘poor’ metabolizers of metoprolol and debrisoquin. The poor metabolizers have an altered CYP2D6 enzyme and exhibit low capacity to hydroxylate many drugs.

 

CYP2C8/9 Important in the biotransformation of >15 commonly used drugs including phenytoin, warfarin which are narrow safety margin drugs, as well as ibuprofen and tolbutamide.

 

CYP2C19 Metabolizes > 12 frequently used drugs including omeprazole, lansoprazole.

 

Rifampicin and carbamazepine are potent inducers of the CYP2C subfamily.

 

CYP1A1/2 Though this subfamily participates in the metabolism of only few drugs like theophylline, it is more important for activation of procarcinogens. Apart from rifampicin and carbamazepine, polycyclic hydrocarbons, cigarette smoke and charbroiled meat are its potent inducers.

 

CYP2E1 It catalyses oxidation of alcohol and formation of minor metabolites of few drugs, notably the hepatotoxic Nacetyl benzoquinoneimine from paracetamol; chronic alcoholism induces this isoenzyme.

 

The relative amount of different cytochrome P450s differs among species and among individuals of the same species. These differences largely account for the marked interspecies and interindividual differences in rate of metabolism of drugs.

 

Barbiturates, phenothiazines, imipramine, ibuprofen, paracetamol, steroids, phenytoin, benzodiazepines, theophylline and many other drugs are oxidized in this way. Few drugs like cimetidine, ranitidine, clozapine are oxidized at their N, P or S atoms by a group of flavinmon ooxygenases that are present in liver, but are distinct from CYPs. They have not been found to be induced or inhibited by other drugs, and thus are not involved in drug interactions. Some other drugs, e.g. adrenaline, alcohol, mercaptopurine are oxidized by mitochondrial or cytoplasmic enzymes.

 

Reduction This reaction is the converse of oxidation and involves cytochrome P450 enzymes working in the opposite direction. Alcohols, aldehydes, quinones are reduced. Drugs primarily reduced are chloralhydrate, chloramphenicol, halothane, warfarin.

 

Hydrolysis This is cleavage of drug molecule by taking up a molecule of water.

                           esterase

Ester + H2O ————→ Acid + Alcohol

 

 

Similarly, amides and polypeptides are hydrolysed by amidases and peptidases. In addition, there are epoxide hydrolases which detoxify epoxide metabolites of some drugs generated by CYP oxygenases. Hydrolysis occurs in liver, intestines, plasma and other tissues. Examples are choline esters, procaine, lidocaine, procainamide, aspirin, carbamazepineepoxide, pethidine, oxytocin.

 

Cyclization This is formation of ring structure from a straight chain compound, e.g. proguanil.

 

Decyclization This is opening up of ring structure of the cyclic drug molecule, e.g. barbiturates, phenytoin. This is generally a minor pathway.

 

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