The chemistry of drug metabolism

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Abstract

Microgynon 30 tablets are a type of hormonal contraception commonly known as 'the pill' or combined oral contraceptive pill. Microgynon 30 tablets contain two active ingredients, ethinylestradiol and levonorgestrel. These are synthetic versions of the naturally occurring female sex hormones, oestrogen and progesterone. Ethinylestradiol (previously spelt ethinyloestradiol in the UK) is a synthetic version of oestrogen and levonorgestrel is a synthetic form of progesterone.

Combined oral contraceptives like Microgynon work by over-riding the normal menstrual cycle. In a woman's normal menstrual cycle, levels of the sex hormones change throughout each month. The hormones cause an egg to be released from the ovaries (ovulation) and prepare the lining of the womb for a possible pregnancy. At the end of each cycle, if the egg has not been fertilised the levels of the hormones fall, causing the womb lining to be shed as a monthly period.

The daily dose of hormones taken in the pill work mainly by tricking your body into thinking that ovulation has already happened. This prevents an egg from ripening and being released from the ovaries each month.

Metabolism is a pharmacokinetic step during which a lipophilic drug is altered to form hydrophobic metabolites either in active or inactive form for easy hepatic or renal elimination. Most chemical change that occurs to administered drug leads to loss of pharmacological activity. Except if the drug is a pro drug e.g. cyclophosphamide

P450 is a family of haem containing compounds found from bacteria to mammals, they are membrane associated protein (endoplasmic and mitochondria) and differs from haemoglobin because of the difference in the fifth ligands; histidine in haemoglobin cysteine in P450. P450 isoenzymes are responsible for large amount of substrate metabolism in mammalian body e.g. natural product, and carcinogens metabolism also. It also plays role in intermediate metabolism such as in prostaglandins, fat soluble vitamins A and D, xenobiotics metabolism.

Humans are not the only organisms with this metabolic activity. Helmintics contains Xenobiotic metabolising enzymes such as oxidases, tranferases reductases, hydrolases used to defend itself from antihelmintics drugs induced by repeated exposure to antihelmintics drugs and they are all effective in any stage of the parasite development2. The same goes for methicillin resistant strand of styphylococoous aureus which is rendered ineffective by Β- lactemase enzymes. In both cases these enzymes develops drug resistance.

The hydrolysis of drug esters and amides functional groups generates carboxylic acids with alcohols and amine respectively. Such metabolites are also susceptible to phase II metabolism.

Introduction

To describe and explain the chemistry of drug metabolism a basic foundation of knowledge is needed to understand the concepts. Metabolism is one of the methods for analysing the effect of drugs or xenobiotics on the body. It is basically a process of converting lipophilic drugs into more hydrophilic drugs to decrease pharmacological effect and increase subsequent hepatic or renal elimination. So it is essentially a process of inactivation and detoxification of a drug and subsequent elimination of the metabolite formed.

The basic knowledge involves the all time classical reactions such as oxidation and reduction and those more advanced reactions including glucuronidation and sulfation. Despite energy being needed to drive such reactions to be in favour, metabolism cannot occur without the complex nature of enzymes catalysing the process. However, metabolism of drugs in human is not solely dependent on the enzymes alone - it can be affected by natural micro flora in the small intestines. In an in vitro experiment conducted on ranitidine, it was found that N-oxide was cleaved and is therefore a source of drug metabolism. An alteration in the population of micro flora can affect the of drugs efficacy - this is a source of interaction between antibiotics and Microgynon®.

Furthermore, some drugs are bioactivated by metabolism to form active metabolites with a desirable pharmacological function i.e. prodrugs. Unfortunately metabolism can transform an inactive drug or xenobiotic into a biologically active compound which can be carcinogenic to humans. Phenol is a readily formed metabolite of benzene metabolism before catechol and hydroquinone 3,6 which poses a major health concern for humans because it can cause acute myelogenous leukaemia 6

As the great founding father of medicine Paracelsus once said "all drugs are poison". Therefore humans and animals have adapted many mechanisms for detoxifying xenobiotics, and these processes are divided into two phases - phase I and phase II. It is important to bear in mind that some phase II reactions can occur without phase I metabolism, but phase I and phase II reactions are complimentary and not mutually exclusive. This report describes the chemical reactions of drug metabolism and explains how they occur in vivo.

Phase 1

Phase 1 metabolism involves the direct enzyme activity on drugs - P450 isoform enzymes and esterases are responsible for reduction and hydrolysis of drugs respectively. Each P450 isoenzyme's genetic expression varies and can either be inhibited or induced. Knowledge of these drivers of metabolism is essential not only to optimise the use of drugs, reduce harm, maximise benefits in poly pharmacy but also to serve as a template for novel drug development10.

P450 and esterase enzymes are mainly found in the liver. Phase I metabolism consists of 3 main reactions: oxidation, reduction and hydrolysis.

Reduction reactions are mainly interconversion reactions that occur in azo, nitro and epoxide groups and conversion of carbonyl to its corresponding alcohol. Reduction reactions are carried out in the body by P450 isoenzymes, NADH/NADPH reduction systems, carbonyl reductase or aldo-ketone reductase.

Azo compounds are generally used in pharmaceutical and cosmetic products. Reduction of an azo group is a classical example of a reduction metabolic reaction. This reaction occurs in the presence of other enzymes and is inhibited in the presence of molecular oxygen.

Mechanism of Azo reduction

Azo reduction can also occur in the presence of NADH/NADPH system alone within the pH range 3.5-6.08. An azo group can either be reduced by 2 hydrogens to form hydrozo compounds or 4 hydrogens to form two aromatic amines which usually results in a colour loss10

Similar reactions occur in the activation of sulphanilamide from its azo compound to form 1, 2, 4 triaminobenzene and itself. Therefore reduction creates a new functional group as shown in figure 3.2.2

Mechanism of Nitro reduction

Nitro groups also undergo reduction reactions and these are catalysed by the same NADP systems. 6 e- are donated to the NO2 to form amine functional groups as in chloramphenicol. This then undergoes acetylation conjugation in phase II metabolism.

Conversion of carbonyl to corresponding alcohols

Many different enzymes have been identified that catalyse carbonyl reduction of xenobiotics, but most of them catalyse other endogenous substances including sugars and prostaglandins7

Oracin, an anticancer drug with a pro-chiral carbon is metabolised by 11 ß-hydroxysteroid dehydrogenase type I in the microsomes. These metabolites are stereo specific to form DHO7 as shown below in figure 3.2.4. Much of what is known about Oracin metabolism is from phase II clinical trials as its not licensed for use in chemotherapy yet.

Mechanism of epoxide reduction

This reaction is catalysed by microsomal epoxide hydrolase, a catalytic triad that consists of His 431, Asp226 and Glu 404. Their activity is limited because of a narrow hydrophobic tunnel in the active site and water.

  • A water molecule ionises to form a - OH and H+
  • OH attacks the oxirane ring and thus opens it resulting in formation of vicinal dihydrodiol.

This reaction is slow in vitro without acid but in this case epoxide hydrolase catalyses the reaction. Vicinal diols formed are more water soluble thereby terminating genotoxic potential.

Hydrolysis

Most hydrolysis reactions occur at the ester and amide functional groups, with ester more prone to hydrolysis than amide. Amides are more stable than esters because nitrogen is similar to carbon in size, but less electronegative than oxygen so electrons are pulled into the carbonyl p electron systems which stabilise its structure. The ease of hydrolysis of esters is used in the development of prodrugs to avoid first pass metabolism, a major problem in orally administered drugs.

In vivo hydrolytic metabolism of drugs occurs in the presence of enzymes present in various parts of the body. Hydrolysis of drugs and xenobiotics is generally carried out by esterases mainly in the plasma and intestine and not by P450 systems. The blood, GI tract and liver have the highest hydrolysing capacity. The most significant hydrolysing enzymes are carboxylesterases, cholinesterases, arylesterases and serine endopeptidases.

Carboxylesterase is one of the major esterases involved in drug metabolism and xenobiotic biotransformation of drugs with esters, amide and thioester functional groups. In figure 3.0 hydrolysis of ester bond results in benzoylecgonine, a carboxylic acid metabolite. But this is not the only ester group present in the structure. The group present next to the benzene can also undergo metabolism to form benzoic acid. Cocaine in the presence of heroine can generate the toxic metabolite cocaethylene in the presence of alcohol, from concomitant cocaine abuse.

Carboxylesterase exists in two different forms - hCE1 and hCE2. hCE1 is a more effective metabolic enzyme which transports protein to the endoplasmic reticulum and processes fatty acids and cholesterol in the liver alongside other cholesterol enzymes.

The general mechanism of drug hydrolysis in esters and amides is by nucleophilic acyl substitution reactions as shown in figure 3.2.6.

Minor structural differences exist between heroine and its metabolites, but their activity differs. Heroin (diamorphine) is converted by hydrolysis to 6-acetylmorphine and morphine. hCE1 mainly cleaves the 3-acetyl linkage to form 6-acetylmorphine. The 6-acetyl linkage is cleaved which later forms morphine with a phenolic -OH and secondary allylic -OH.

Diloxanide furorate is a drug of choice and an antiparasitic agent for treating asymptomatic patients with E. histolytica cysts in the faeces and cryptosporidiosis, an acute intestinal amoebiaosis in HIV patients. The drug is orally administered and extensively metabolised by gastro intestinal esterase to form diloxanide and furoic acid, thereby diminishing its effectiveness. This problem is modified by using cyclodextrin that prevents excessive hydrolysis of the drug.

Carboxylesterase's ability to form a stable complex enhances its presence in the blood and makes it ideal for treating cocaine overdose. It is also considered that as an active site for drugs, this would make it ideal for drug discovery e.g. sarin and VX gas.

Phase II Conjugation pathway

The phase II conjugation pathway is often a detoxification mechanism. It terminates drug pharmacological activity by changing or masking functional groups in the parent drug or phase I metabolite into a more ionic polar product which aids excretion. The processes that commonly occur in phase II metabolism can be fundamentally divided into 3 groups which are glucuronidation, sulfation and acetylation. The nature and functional group of a drug molecule will determine which one of these processes be in favour e.g. acetaminophen undergoes both glucuronidation and sulfation, however at high doses glucuronidation predominates and at low doses sulfation predominate (Airpine & Choonara, 2009).

Conjugation with sugars

Conjugation with various sugars is possible in nature, and novel pathways for xenobiotic metabolism are discovered frequently (Ikenakaa, Ishizakab, & Miyabaraa, 2007). However the most important reaction in humans is glucuronidation.

Glucuronidation

Glucuronidation is essentially conjugation of a substrate with a-D-glucuronic acid, shown in figure 4.1.1.1. As the name suggests, glucuronic acid is a derivative of glucose with the 6th carbon being oxidised to a carboxylic acid group. This in combination with the many hydroxyl groups gives glucuronic acid a solubility of 1g/10mL in cold water, which the British Pharmacopeia would class as "freely soluble" (British Pharmacopeia Commission, 2009)

Glucuronic acid is present in vivo as the co-factor uridine 5'-diphosphate-glucuronic acid (UDP-glucuronic acid). The reaction of UDP-glucuronic acid with a xenobiotic substrate is catalysed by the enzyme UDP-glucuronosyltransferase (UGT) (Kaeferstein, 2009), and an example of a glucuronidation reaction is shown in figure 4.1.1.2

Figure 4.1.1.2 demonstrates how glucuronidation can occur with a xenobiotic containing an acceptor nucleophilic group (for example COOH, SH or NH2, but in this case OH) (Kaeferstein, 2009) (Sakaguchi, Green, Stock, Reger, & King, 2004). The lone pair of electrons on the hydroxyl group attacks at the 1st carbon of the pyranose ring, which is activated because of the adjacent electron-withdrawing oxygens, in an SN2 nucleophilic substitution reaction. The UDP glycosidic bond is cleaved off owing to the good leaving group properties of the phosphate group, and the xenobiotic has reacted with the glucuronic acid to form a ß-D-glucopyranosiduronic acid conjugate. Note that the reaction is known to be SN2 because the formation of an intermediate leads to an inversion of stereochemistry at the anomeric carbon.

The resulting glucuronide conjugate has improved solubility due to the hydroxyl and carboxylate groups, and is usually excreted in the urine, although there is evidence to suggest that conjugates with a high molecular weight are eliminated in the bile. However the glucuronides undergo some important reactions within the body which affects their metabolism. A spontaneous intramolecular reaction can lead to esterification of the glucuronide, as shown in figure 4.1.1.4. The newly formed ester carbonyl is capable of reacting with the N-terminal of a protein residue to form a stable imine, i.e. this can lead to irreversible protein binding. Alternatively, depending on which species the glucuronic acid is bound to, nucleophilic substitution can again occur and the xenobiotic will react with the N-terminal of the protein and regenerate free glucuronic acid (Zamek-Gliszczynski, Hoffmaster, Nezasa, & Brouwer, 2006).

Pharmaceutical companies may therefore try to avoid designing drugs which are predicted to be metabolised by the glucuronidation pathway, not just to increase the half-life of the drug by avoiding conjugation and excretion but also to avoid the potential side-effects that can occur as a result of protein binding, such as cirrhosis of the liver.

Interestingly, glucuronidation can also lead not just to metabolites that lose their therapeutic use and are toxic, but some glucuronides can continue to be pharmacologically active and may even be more potent than their parent drug.

Morphine-6-glucuronide (M6G) is one such example. M6G and morphine are both potent analgesics - M6G, despite having been conjugated with a large polar molecule, still binds strongly to µ opioid receptors to provide pain relief to the same extent as morphine. Morphine-3-glucuronide, another metabolite, binds preferentially to NMDA receptors instead, and causes allodynia, myoclonus and seizures (the side-effects associated with opiate usage). Morphine and codeine are so far the only known examples of glucuronides with high activity (Kaeferstein, 2009).

Glutathione conjugation

Glutathione serves as a substrate for electrophilic drugs because of the nucleophilic thiol moiety on the cysteine residue (thus glutathione can be referred to in reaction pathways as simply GSH). GSH conjugation therefore involves a nucleophilic attack of the sulphur atom onto drugs with electrophilic carbon atoms, i.e. those bound to good leaving groups such as halogens, sulphate and nitro, as well as activated carbon atoms in ring strained systems such as epoxides and ß-lactones (Zamek-Gliszczynski, Hoffmaster, Nezasa, & Brouwer, 2006).

Conjugation leads to a thioether bond being formed between GSH and the drug molecule. Following this reaction, conjugates are typically metabolised further to yield more polar molecules which are better excreted in the urine and bile (Zamek-Gliszczynski, Hoffmaster, Nezasa, & Brouwer, 2006).

Alternatively, two molecules of glutathione can react together to form a disulfide bridge, in the process donating hydrogen atoms to reduce another molecule. This is usually utilised in vivo when glutathione acts as an antioxidant (Forman, Zhang, & Rinna, 2009), but also plays a part in drug metabolism as seen in the denitrification of the antianginal drug, glyceryl trinitrate (GTN) in figure 4.2.5 (Ji, Anderson, & Bennett, 2009).

To reiterate, GSH reacts with highly electrophilic species in the body. This prevents drugs with electrophilic groups from attacking important nucleophilic centres in biological molecules, such as DNA and proteins, which could lead to toxicity. This is explored further in section 5 where the consequences of insufficient glutathione conjugation of paracetamol metabolites are looked at.

Sulfation

Sulfation is one of the classical processes of phase II metabolism. It allows the biotransformation of numerous xenobiotics and metabolites from phase 1 (shown in figure 4.3.1) to be sulphate conjugates.

This gives protection against toxicity or the potential toxic effects from the numerous xenobiotics and metabolites not being conjugated. It also produces more polar, more water soluble metabolites, which means they are more easily and readily excreted in urine or bile. The sulphate conjugate possesses such advantageous properties by having a low pKa, allowing an increased aqueous solubility and excretion. It is an important reaction for drugs and hormones that contain the phenolic functional group to be metabolised by conjugation to a sulphate group - examples include steroid hormones, catecholamines, neurotransmitters, thyroxine, bile acids and phenolic drugs.

The chemistry behind the sulfation conjugation reaction emphasizes the important key features of the system. This includes the two enzymes sulfatase and sulfotransferase, alongside the co factor 3'-phosphoadenosine 5'-phosphosulfate (3'-phosphoadenylylsulfate, PAPS) which plays an important role in sulfation conjugation. The availability of PAPS and its precursor inorganic sulphate determines the reaction rate as the total amount of sulphate is limited and can be readily used up. PAPS is formed enzymatically by ATP and inorganic sulphate. The enzyme sulfotransferase transfers the active sulphate from PAPS to the xenobiotic or a phase 1 metabolite forming the sulphate conjugate (VL & Verdugo D, 2004). Sulphate conjugation is a reaction principally of phenols and to a lesser extent alcohols to form highly ionic polar sulphates. Sulphate conjugation is also important for steroids because steroid sulphates are not capable of binding to their receptor and so this reduces its biological activity. Sulfation of alcohol generates a good leaving group and can be an activation process for alcohols to produce a reactive electrophilic species.

Mechanism of sulfation conjugation - an electrophilic substitution reaction:

  • The oxygen of the OH has a negative inductive effect on the benzene ring so it withdraws electrons towards it making it a more reactive nucleophile
  • It attacks the electrophilic sulphur of the sulphate group of PAPS
  • The hydrogen of the OH bond leaves in exchange for the sulphate group and UDP acts as a good leaving group
  • This forms the sulphate conjugate which is soluble and readily excreted via the kidneys

Acetylation Conjugation

Acetylation is also an important reaction in phase II metabolism as the majority of drugs contain a primary amine functional group. It is a major route for the biotransformation of hydrazine and aromatic amines. This means that acetylation of the arylamine or phase 1 metabolites can occur more easily to reduce their biological activity (Garcia-Galan & Diaz-Cruz, 2008). The limitation of acetylation is that it produces conjugates that are less water soluble (Zamek-Gliszczynski, Hoffmaster, Nezasa, & Brouwer, 2006) as well as it does not work for drugs containing secondary amine groups. The aim of acetylation is to convert the primary amine moiety into an amide because amides are more stable as peptide bonds are more resistant to hydrolysis. Like glucuronidation and sulfation this reaction is highly specific because of the nature of the enzyme involved. The main players of acetylation conjugation are N-acetyltransferase and the co factor acetyl Coenzyme which is a thioester . The reaction undergoes electrophilic substitution similar to Friedal-Craft acylation. The NH2 attached to the aromatic ring makes it much more reactive and electron donating. NAT helps to transfer the acetyl group (CH3CO) obtained from Co enzyme A (CH3COSCoA) to conjugate with the drug at the amine site forming the amide bond. H-SCo-enzyme acts as a good leaving group.

Mechanism of acetylation conjugation:

  • The lone pairs of the nitrogen of the primary amine of sulphonamide attack the carbonyl carbon of the acetyl group of the acetyl coenzyme A. In this reaction nitrogen acts as a nucleophile, donating the pair of electrons to the electrophilic carbonyl carbon. The carbonyl carbon (d+) is activated by the electron withdrawing oxygen (d-) making it more susceptible to nucleophilic attack.
  • This forms a temporary tetrahedral intermediate, which falls back to form an amide bond and SH-CoA acts as a leaving group.
  • As a result the acetyl conjugation of sulphonamide is formed, and this is readily excreted via the kidneys.

Stereo selectivity

Stereo selectivity is classed as a fundamental aspect of drug metabolism ever since the tragic case of the drug thalidomide. This has provided a broader knowledge on the understanding of drugs and xenobiotics and also the importance of their stereochemistry properties.

As mentioned in section 4.1.1 (glucuronidation), drug metabolism may lead to stereochemistry inversion of substrates during the various reactions that occur. An example of how the understanding of stereochemistry in xenobiotic metabolism has practical applications can be seen with the non-steroidal anti-inflammatory drug ibuprofen.

It has been found that in vitro, only the S-isomer is pharmacologically active in inhibiting cyclooxygenase enzymes. However in vivo the metabolism of ibuprofen is complex, involving glucuronidation at the acyl group and hydroxylation at the 2 and 3 positions, but most importantly the metabolism of the 2 enantiomers differs because there is a unidirectional enzymatic conversion of the R-isomer to the active S-isomer. (Chang, et al., 2008). The metabolism of ibuprofen is summarised in figure 4.5.2.

For this reason drug manufacturers typically produce a racemic mixture of ibuprofen for administration to patients, since the R-isomer will be converted within the body, and producing an enantiomerically pure sample would be needlessly expensive.

Micellaneous

Amino acid conjugation is important for metabolising, solubilising and eliminating carboxylic acids through the urine because it produces very soluble conjugates.

Amino acid conjugation mechanism e.g. benzoic acid (Xu, et al., 2007):

  • The carboxylic group of the benzoic acid is first activated by ATP to the AMP ester
  • This is then converted to the corresponding coenzyme A thioester with CoASH.
  • These first two steps are catalysed by acyl Coenzyme A synthase enzyme
  • The appropriate amino acid N-acyltransferase then catalyses the condensation of amino acid and Coenzyme A thioester to form the amino acid conjugate.

Methylation conjugation: Even though it is not a common reaction for most drugs and xenobiotics, it is worth mentioning methylation because it is the most common biochemical reaction for endogenous compounds such as catecholamines (Strous, et al., 2009). Methylation plays a key role in the inactivation of amines such as norepinephrine, serotonin, dopamine and histamine, and is also involved in the biosynthesis of epinephrine and melatonin. A source of methyl comes from the high energy nucleotide S- adenosylmethionine (SAM) which is transported by cathecol-O- methyltransferase. However, it has been reported that methylated conjugates do not have improved water solubility (a similar disadvantage to acetylation).

Methylation mechanism - the nucleophilic substitution of norepinephrine:

  • The lone pair on the electronegative oxygen of norepinephrine (R-OH) attacks the CH3 of SAM
  • The bond between the sulphur and carbon breaks (S-C)
  • Hydrogen cleaves off and the O-CH3 bond form, with the methyl CH3 taking up the position of the hydrogen.

Drug Toxicity

The toxicity associated with acute paracetamol overdose is due to its metabolism processes. In the human body, paracetamol is mostly metabolised - 30% by the sulfation pathway, 60% via glucuronidation and the remaining 10% being either excreted unchanged in the urine or undergoing CYP450-dependent oxidation as shown in figure 5.3 to form N-acetyl-p-benzoquinoneimine (NAPQI) (Airpine & Choonara, 2009).

NAPQI contains an electronically activated ring system, capable of attacking nucleophilic molecules such as N atoms in cellular macromolecules and causing cell damage. However NAPQI will preferably attack the more nucleophilic sulphur atom of glutathione and therefore will also undergo phase II metabolism to form inactive conjugates - a schematic summary of the metabolism of paracetamol is shown in FIGURE 5.4

In overdose situations, the glutathione supply is used up as it is conjugated with the excessive NAPQI in the system. This leaves the rest of the NAPQI free to bind irreversibly to proteins in hepatic liver cells (since P450 metabolism occurs predominantly in the liver) and this cause liver necrosis. Without the detoxification capacity of the liver, the human body will typically die within 2 weeks (Airpine & Choonara, 2009).

With the chemistry of paracetamol metabolism in mind, it is easier to understand why some patients are classed as "high-risk" and thus more susceptible to paracetamol overdose:

  • Recent alcohol (ethanol) consumption causes induction of the P450 enzyme involved in the formation of the NAPQI molecule; this leads to an increased quantity of NAPQI being produced and therefore the body's supply of glutathione for conjugation is more rapidly used up leading to toxicity. Other drugs which induce the same P450 enzymes will have the same effect.
  • Eating disorders such as anorexia nervosa lead to a poor diet and therefore decreased synthesis of glutathione in vivo, so NAPQI detoxification conjugation can be overwhelmed at lower concentrations of paracetamol consumption.

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