Explaination of drug metabolism.
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 drug to elicit pharmacological effect and subsequent hepatic or renal elimination. So it is essentially a process of inactivating, detoxification (Oracin) of a drug and subsequent elimination of a drug metabolite formed.
However some drugs are bioactivated by metabolism to form an active metabolite with a desirable pharmacological function (prodrug).unfortunately, metabolism can transform an inactive drug or xenobiotic into a biologically active compound which can be carcinogenic to human. Phenol is a readily formed metabolite of benzene metabolism before catechol and hydroquinone 3,6which posses a major health concern for human because it can cause acute myelogenous leukaemia 6
Metabolism and biotransformation occurs and are catalysed by specialised enzymes. 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
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For an orally administered drug, absorption must take place to produce therapeutic effect. This absorption determines its bioavailability and also determines the level of interaction of the drug. Metabolism of drug 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 which result in the loss of oxygen atom and so 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 Microgynom®
Direct enzymes activities on drugs are mainly the driving force of drug metabolism, P450 isoform enzymes and esterases are responsible for reduction and hydrolysis of drugs respectively. Each P450 isoenzymes 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 development9.
P450 and esterase enzymes are mainly found in the liver. Phase I metabolism consists of 3 main reactions; Oxidation, reduction and hydrolysis. In this part of phase I reactions. Reduction and hydrolysis would be discussed.
Reduction reactions are mainly interconversion reactions that occur in Azo, Nitro and epoxide groups. 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.
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.
Azo compounds are generally used in the pharmaceutical and cosmetic products. Reduction of an azo group is a classical example of reduction metabolic reactions. This reaction occurs in the presence of and or other enzymes and inhibited in presence of molecular oxygen.
Mechanism of Azo reduction
Azo reduction can also occur in the presence of NADH/NADPH system alone within pH 3.5-6.0. Azo group can either be reduced by 2 hydrogen to form hydrozo compounds or 4 hydrogens to form two aromatic amines which usually results into a colour loss
Similar reaction occurs in the activation of sulphanilamide from its azo compound to form 1, 2, 4 triaminobenzene and itself. So reduction creates a new functional group
Mechanism of Nitro reduction
Nitro groups also undergo reduction reactions and this is catalysed by the same NADP systems 6e- is donated to the NO2 to form amine functional group as in chloramphenicol.
Many different enzymes had been identified that catalyse carbonyl reduction of xenobiotics but most of them catalyse other endogenous substances including sugars and prostaglandin7
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Oracin an anticancer drug with a pro chiral carbon is metabolised by 11 ?-hydroxysteriods dehydrogenase type I in the microsomes. These metabolites are stereo specific to form DHO7 as shown below.
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
Reaction is catalysed by microsomal epoxide hydrolase a catalytic triad that consist of His 431, Asp226 and a Glu 404. There activity is limited because of narrow hydrophobic tunnel of the active site and water.
- 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 hydrolases catalyse the reaction. Vicinal diol formed are more water soluble thereby terminates genotoxic potential.
Most hydrolysis reactions occur at the ester and amide functional groups with ester more prone to hydrolysis reaction than amide. Amide is more stable than esters because nitrogen is similar to carbon in size, but less electronegative than oxygen so electrons are pulled into the carbonyl ? electron systems which stabilise its structure. The ease of hydrolysis of esters is used in the development of pro drugs 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 part of the body. Hydrolyses of drug and xenobiotics is generally carried out by esterases mainly in the plasma and intestine and not by P450 systems. The blood, G.I 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 esterase involved in drug metabolism and xenobiotics biotransformation of drugs with esters, amide and thioesters functional groups. In figure (3.0) hydrolysis of ester bond resulted 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 toxic metabolite cocaethylene in the presence of alcohol form contaminant cocaine abuse.
Carboxylesterase exists in two different forms hCE1 and hCE2. The first isoform hCE1, is more effective metabolic enzyme which transports protein to the endoplasmic reticulum and process fatty acids and cholesterol in the liver alongside other cholesterol enzymes. Cocaine and heroin. From its reactions, it can a generate a toxic metabolite cocaethylene in the presence of alcohol from contamitant cocaine abuse1
General mechanism of drug hydrolysis of esters and amide is by nucleophilic acyl substitution reactions
Minor structural differences exist between heroine and its metabolites. But there activity differs Heroine is converted by hydrolysis to 6-acetylmorphine and morphine. hCE1 mainly cleaves 3 acetyl linkage to form 6-acetylmorphine.6 acetyl linkage is cleaved which later forms morphine with phenolic -OH and secondary allylic -OH.
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.
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 there by diminishing its effectiveness. This problem is modified by using cyclodextrin that prevent excessive hydrolysis of the drug.
Carboxylesterase ability to from a stable complex enhances its presence in the blood and ideal for treating cocaine overdose. It is also considered as an active site for drugs would make it ideal for drug discovery e.g. Sarin and VX gas.
Metabolism and biotransformation occurs and are catalysed by specialised enzymes. 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.
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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 ?- lactemase enzymes. In both cases these enzymes develops drug resistance.
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.
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- Joanna Kowalo'ska-Zawieja et al, Barbara Zielin'ska-psuja,Andrzej Plewka (2003) metabolic interactions between acetylsalicylic acid and benzene. Toxicology Vol. 188( 2-3) pp 161-170.
- Vladimir Wsol,Barbora Szotakova,Hans-joerg martins,Edumund Maser ( 2007) Aldo keto reductases form the AKR1C subfamily catalyze the carbonyl tredution of the novel anticancer drug Oracin in man . Toxicology Vol .238(2-3 ) pp 111-118.
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