The role of drug metabolism is to modify the functional group of a drug molecule to make it more water soluble (e.g. by making it more polar), which makes it more readily excreted by the kidneys (i.e. the body try to get rid of the "chemical invader"). As the drugs molecule enters the body, it will be attacked by a range of metabolic enzymes, and the reaction result in the formation of metabolites. These metabolites can either lose the activity of the parent drug, or possess different activity which may cause toxicity or unwanted side effects. Also, the drug metabolism may activate a drug molecule in the body, which is known a pro-drug strategy.
One of the enzymes involved in drug metabolism is cytochrome P450 (found in the liver), which is able to add a polar group to a range of drugs. Other enzymes may reveal a masked polar group that is already present in the drug (e.g. demethylation of methyl ether to reveal a hydroxyl group).
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The end result of drug metabolism is to eliminate the drug from the body as either unchanged form or through conversion to metabolites. This process where the drug is converted to a metabolite is called biotransformation, and they are classified as Phase I (functionalization reactions) and Phase II (conjugation reactions).
Phase I reactions involve the introduction of a functional group to the drug molecule, which result in either loss pharmacological activity or active intermediate metabolites (as in the case of produrgs). Phase I generally involve oxidation, hydrolysis and reduction. The majority of these reactions happen in the liver, although some of them (e.g. hydrolysis of amides and esters) can occur in a different place, such as blood plasma or gut walls. The reactions can happen inside the cell, i.e. endoplasmic reticulum and cytosol, but other places are also common such as the plasma membrane or mitochondria.
On the other hand, phase II reactions form a covalent link between the functional group on the original molecule with glucuronic acid, glutathione, acetate etc. These conjugates are inactive and very polar which means they will be excreted easily in the urine or faeces. Most of the reactions are conjugation reactions by transferase enzymes, and glucuronic acid conjugation is the most common reaction.
It is now a requirement to establish studies on drug metabolism to identify all its metabolites before the drug can be approved. This is due to the fact that some drugs can form more than two metabolites while other drugs might not be metabolised at all. Knowledge of the possible metabolic reactions for various functional groups aid the medicinal chemist to predict the metabolic pathway or product, and therefore allow him to design new drugs which do not have unwanted metabolites.
Oxidation is the most common type of biotransformation in drug metabolism; it includes aromatic hydroxylation, aliphatic hydroxylation, epoxidation and other reactions. All the reactions involve an initial insertion of an oxygen atom into the drug molecule followed by rearrangement. Here are some examples of hydroxylation reaction that occurs in the body:
1) Conversion of lignocaine (antidysrhythmic and local anaesthetic) to the 3-hydroxy derivative
2) Hydroxylation of pentobarbitone
3) Epoxidation of benzo(a)pyrene to its 4,5-epoxide
Usually, aliphatic compounds do not get oxidised unless a primary/secondary alcohol or aromatic side chain formed. If a drug can be metabolized either by aromatic hydroxylation or aliphatic hydroxylation then aliphatic hydroxylation is always predominant.
The mechanisms of aromatic hydroxylation involve an epoxide intermediate as the first step, followed by NIH shift (NIH is called after the U.S. National Institute of Health where it was discovered). The reaction is catalysed by cytochrome P450.
A radical iron-Oxo species delivers oxygen. The rate of ring-opening depends on the intermediates stability. In addition, aromatic hydroxylation is faster for electron-rich rings than electron-poor rings.
The NIH shift is an intramolecular migration of a substituent group at the site of oxidation which moves to an adjacent ring position, and can affect halogenated substituent (e.g. chloro- and fluro-). This can occur in both enzymatic and chemical hydroxlations, where the NIH shift derives from rearrangement of arena oxide intermediate in enzymatic reactions, (although other pathways can occur). Hydroxylation at the D position can lead to a migration of the substituent (if the R group is not readily ionziable e.g. CH3 and OCH3). It can also cause loss of substituent, (the competing pathway without D).
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When a drug molecule contains a benzene ring, it can undergo aromatic hydroxylation to get metabolised to an epoxide intermediate first. After that, there are two reactions than can occur. In the first reaction, the epoxide undergo non-enzymatic rearrangement to phenol as the major metabolite phenol (with pKa=10 and less than 1% ionized at pH 7.4). the phenol the undergo glucuronidation to phenyl glucuroide (with pHa=3.4), which is very water soluble because more than 99% ionized at pH 7.4.
In the second reaction, the epoxide gets attacked epoxide hydrolyase to get 1,2-dihydro-1,2-diol which then get converted to catechol.
In recent studied, it has been shown than benzene can be a possible carcinogen, due to the production of a reactive oxygen species from one of its metabolites. A recent study reviewed the mechanism if antiapoptotic effects (that leads to prolonged cell survival) by the benzene metabolite, hydroquinone and p-benzoquinone. These metabolites were found to cause serum starvation and lack of an extracellular matrix which result in inhibit of apoptotic death of NIH3t3 cells. It has also been reported that benzene metabolites can cause carcinogenesis by inducing deregulation of apoptosis which is due an inhibition of caspase-3 (caspase is protein that plays a central role in execution phase of cell apoptosis).
Hydroxylation of phenols is quite interesting, as when the the free postion is para to the first hydroxyl group, it will be hydroxylated faster than the ortho-postion. An example of a drug than behave like this pattern is salicylamid, where around half of the administered dose is hydroxylated to 5-hydroxylate metabolite and 20% is 3-hydroxylated.
Mammalian carboxylesterases (CESs) play an important role in the hydrolytic biotransformation of various therapeutic agents that contain an ester or amide bond. They can be found in various mammals and are classified into 5 groups (CES1-5), where the majority belong to CES1-2. CES1 and CES2 are significantly different, e.g. CES mainly hydrolyses a substrate with small alcohol group and large acyl group, while CES2 hydrolyse large alcohol groups and small acyl groups. The substrate specificity is due to restriction by the capability of acyl-enzyme conjugate formation due to the presence of conformational interference in the active pocket. For example, Oseltamivir, antiviral ester prodrug, achieve its activity through its hydrolytic metabolite (oseltamivir carboxylate) which is the product from the hydrolysis of CES1, which also hydrolyse other drugs such as delapril, methyl ester of cocaine, meperidine and the ethyl esters of temocapril.
The mechanism of CES can be divided into the following steps:
1. In the first step, the substrate enters the active site of the enzyme and forms an enzyme-substrate complex. This will position the substrate in a correct orientation ready for the reaction.
2. Thereafter, the hydrolysis starts by a nucleophilic attack from the oxygen of the hydroxyl group of Ser203 on the carbonyl of the ester bond.
3. Gly123 and Gly124 stabilize the negatively charged oxygen through hydrogen bonding of the N-H groups and the oxygen of the tetrahedral intermediate. The hydrogen bonding of two NH groups to negatively charged carboxyl oxygen is called oxyanion hole.
The acid catalysed step results in breaking the ester bond and the leaving group picks up a proton from the imidazolium ion of the Hi450. The acyl part of the original ester remains bonded to the enzyme as an acyl-enzyme intermediate. The acylation step is completed when the alcohol group (R'-OH) diffuse away.
4. In this step, a second tetrahedral intermediate is formed following an attack from a water molecule on the acyl-enzyme intermediate.
5. Thereafter, His450 donates a proton to the oxygen of Ser203. This will result in the release of the acid portion of the substrate, which then diffuse away and the enzyme is ready for catalysis. Stabilization of the tetrahedral transition state is due low barrier hydrogen bonds formed between His450 and Glu336. This low barrier hydrogen bonding promote weak hydrogen bonding between the O- and NH groups (from Gly123 and 124), which stabilize the tetrahedral adduct on the substrate side of the transition state.
In the next step removal of a proton from His450 disrupt the tetrahedral intermediate which results in the formation of acyl-enzyme intermediate. A second step, deacylation, occurs when the unbound portion of the alcohol group of the first product of the substrate diffuse away. Deacylation is the reverse of the acylation where a water molecule substitutes the alcohol group of the original substrate.
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