These reactions generally precede phase II reactions and include oxidative, reductive and hydrolytic reactions.
Generally the polar groups are added to the xenobiotics.
Called “Non Synthetic Reactions” as the product is not totally altered.
The primary objectives phase I reactions are,
1. Increase in hydrophilicity
2. Reduction in stability
3. Facilitation of conjugation (Phase II).
Outcome of the Phase I reactions may be active, more active or inactive metabolites.
These reactions are termed non-synthetic reactions, and include oxidation, reduction, hydrolysis, cyclization and decyclization reactions.
These reactions are carried out mostly by mixed function oxidases, usually involving CYP450 and occur in the liver.
In these reactions, a polar group is either introduced or unmasked if
already present.
These reactions are succeeded by Phase II reactions.
Most of the Phase I products are not eliminated directly; instead they undergo Phase II reactions.
Various Phase I reactions are as follows, with several examples:
Oxidation:
Oxidation of aromatic moieties.
Oxidation of olefins.
Oxidation at benzylic, allylic carbon, carbon atoms α to carbonyl and imines.
Oxidation at aliphatic and alicyclic carbon.
Oxidation involving carbon-heteroatom systems:
Carbon-nitrogen systems:
aliphatic and aromatic amines;
N-dealkylation,
oxidative deamination,
N-oxide formation,
N-hydroxylation.
Carbon-oxygen systems:
O-dealkylation
Carbon-sulfur systems:
S-dealkylation,
S-oxidation, and
Desulfurization
Oxidation of alcohols and aldehydes •
Other miscellaneous oxidative reactions
B) Reductive Reactions:
Reduction of aldehydes and ketones
Reduction of nitro and azo compounds
Miscellaneous reductive reactions
C) Hydrolytic Reactions:
Hydrolysis of esters and amides
Hydration of epoxides and arene oxides by epoxide hydrolase.
Oxidation Reactions.
1) Oxidation of aromatic moieties:
Monosubstituted benzene derivatives can be hydroxylated at ortho-, meta- or para-positions but para-hydroxylated product is most common,
e.g. conversion of acetanilide to paracetamol, and phenylbutazone to oxyphenbutazone.
2) Oxidation of Olefins:
A better known example of olefinic oxidation is conversion of carbamazepine to carbamazepine-10,11-epoxide; the latter is converted to corresponding trans-10,11-dihydrodiol.
3) Oxidation of Benzylic Carbon Atoms:
Carbon atoms attached directly to the aromatic rings (benzylic carbon atoms) are hydroxylated to corresponding carbinols.
If the product is a primary carbinol, it is further oxidized to aldehydes and then to carboxylic acids, e.g. tolbutamide.
A secondary carbinol is converted to ketone.
4) Oxidation of Allylic Carbon Atoms:
Carbon atoms adjacent to olefinic double bonds (are allylic carbon atoms) also undergo hydroxylation in a manner similar to benzylic carbons, e.g. hydroxylation of hexobarbital to 3'-hydroxy hexobarbital.
5) Oxidation of Carbon Atoms Alpha to Carbonyls and Imines:
Several benzodiazepines contain a carbon atom (C-3) alpha to both carbonyl (C=O) and imino (C=N) functions which readily undergo hydroxylation, e.g. diazepam.
6) Oxidation of Aliphatic Carbon Atoms (Aliphatic Hydroxylation):
Alkyl or aliphatic carbon atoms can be hydroxylated at two positions - at the terminal methyl group (called as -oxidation) and the penultimate carbon atom (called as -1 oxidation) of which the latter accounts for the major product, e.g. valproic acid.
7) Oxidation of Alicyclic Carbon Atoms (Alicyclic Hydroxylation):
Cyclohexane (alicyclic) and piperidine (non aromatic heterocycle) rings are commonly found in a number of molecules, e.g. acetohexamide and minoxidil respectively.
Such rings are generally hydroxylated at C-3 or C-4 positions.
8) Oxidation of Carbon-Nitrogen Systems:
A) N-Dealkylation:
Alkyl groups attached directly to nitrogen atom in nitrogen bearing compounds are capable of undergoing N-dealkylation reactions, e.g. secondary and tertiary aliphatic and aromatic amines, tertiary alicyclic amines and N-substituted amides and hydrazines.
Tertiary nitrogen is more rapidly dealkylated in comparison to secondary nitrogen because of its higher lipid solubility. Thus, one alkyl from a tertiary nitrogen compound is removed rapidly and the second one slowly.
B) Oxidative Deamination:
Like N-dealkylation, this reaction also proceeds via the carbinolamine pathway but here the C-N bond cleavage occurs at the bond that links the amino group to the larger portion of the drug molecule.
C) N-Oxide Formation:
N-oxides are formed only by the nitrogen atoms having basic properties.
Thus, amines can form N-oxides but amides cannot.
Generally, the tertiary amines yield N-oxides.
N-Hydroxylation:
Converse to basic compounds that form N-oxides, N-hydroxy formation is usually displayed by non-basic nitrogen atoms such as amide nitrogen, e.g. lidocaine.
N-hydroxylation of amides often leads to generation of chemically reactive intermediates capable of binding covalently with macromolecules, e.g. paracetamol.
Paracetamol is safe in therapeutic doses since its reactive metabolite iminoquinone is neutralized by glutathione.
However, in high doses, the glutathione level becomes insufficient and significant covalent tissue binding thus occurs, resulting in hepatotoxicity.
9) Oxidation of Carbon-Sulfur Systems:
A) S-Dealkylation:
The mechanism of S-dealkylation of thioethers (RSR’) is similar to N-dealkylation i.e. it proceeds via -carbon hydroxylation.
The C-S bond cleavage results in the formation of a thiol (RSH) and a carbonyl product, e.g. 6-methyl mercaptopurine.
B) Desulphurization:
This reaction also involves cleavage of the carbon-sulfur bond (C=S or thiono).
The product is the one with a C=O bond.
Such a desulphurization reaction is commonly observed in thioamides (RCSNHR’) such as thiopentone.
C) S-Oxidation:
Apart from S-dealkylation, thioethers can also undergo S-oxidation reactions to yield sulfoxides which may be further oxidized to sulfones (RSO2R).
Several phenothiazines, e.g. chlorpromazine, undergo S-oxidation.
10) Oxidation of Carbon-Oxygen Systems:
O-Dealkylation: This reaction is also similar to N-dealkylation and proceeds by α-carbon hydroxylation to form an unstable hemiacetal intermediate which spontaneously undergoes C-O bond cleavage to form alcohol and a carbonyl moiety.
11) Oxidation of Alcohol, Carbonyl and Carboxylic Acid:
These reactions are mainly catalyzed by non-microsomal enzymes, dehydrogenases.
Primary and secondary alcohols and aldehydes undergo oxidation relatively easily but tertiary alcohols, ketones and carboxylic acids are resistant since such a reaction involves cleavage of C-C bonds.
Primary alcohols are rapidly metabolized to aldehydes (and further to carboxylic acids) but oxidation of secondary alcohols to ketones proceeds slowly.
12) Miscellaneous Oxidative Reactions:
A) Oxidative Aromatisation/Dehydrogenation:
B) Oxidative Dehalogenation:
Reduction Reactions.
Bio-Reductions are also capable of generating polar functional groups such as hydroxy and amino which can undergo further biotransformation or conjugation.
A number of reductive reactions are exact opposite of oxidation. For example:
Alcohol dehydrogenation ↔ Carbonyl reduction
N-Oxidation ↔ Amine oxide reduction.
Reduction of Carbonyls (Aldehydes and Ketones):
Few aldehydes undergo reduction because such a reaction is usually reversible, and secondly, they are susceptible towards oxidation which yields more polar products.
Several ketones undergo reduction as it results in more polar metabolites.
Reduction of aldehydes and ketones yields primary and secondary alcohols respectively.
The reaction is catalyzed by non-microsomal enzymes called aldo-keto-reductases.
Reduction of Alcohols and Carbon-Carbon Double Bonds:
Reduction of norethindrone, an , -unsaturated carbonyl compound, results in both reduction of C=C double bond and formation of alcohol.
Reduction of N-compounds (Nitro, Azo and N-Oxide):
The N-containing functional groups that commonly undergo bioreduction are nitro, azo and N-oxide.
It is the reverse of oxidation.
Miscellaneous Reductive Reactions:
A) Reductive Dehalogenation:
This reaction involves replacement of halogen attached to the carbon with the H-atom, e.g. halothane.
B) Reduction of Sulfur Containing Functional Groups:
An example of S-S reductive cleavage is disulfiram.
HYDROLYTIC REACTIONS.
The hydrolytic enzymes that metabolize xenobiotics are the ones that also act on endogenous substrates.
Moreover, their activity is not confined to the liver as they are found in many other organs like kidney, intestine, etc.
A number of functional groups are hydrolysed viz. esters, ethers, amides, hydrazides, etc.
Hydrolysis of Esters and Ethers:
Esters on hydrolysis yield alcohol and carboxylic acid.
The reaction is catalyzed by esterases.
Aromatic esters are hydrolysed by arylesterases and aliphatic esters by carboxylesterases.
Hydrolysis of Amides (C-N bond cleavage):
Amides are hydrolysed slowly in comparison to esters.
The reaction, catalyzed by amidases, involves C-N cleavage to yield carboxylic acid and amine.
Hydrolytic Cleavage of Non-aromatic Heterocycles:
Non Aromatic heterocycles also contain amide functions, e.g. lactams (cyclic amides), e.g. Penicillins.
Hydrolytic Dehalogenation:
Chlorine atoms attached to aliphatic carbons are de-halogenated easily, e.g. DDT.
Commonly Asked Questions.
Define Biotransformation of drugs. Write a short note on “Phase I Reactions”.