A Study On Adverse Drug Reactions Biology Essay

The intent of composing this paper is to reexamine the polymorphism of human CYP2C19 and its clinical impact. CYP2C19 enzyme metabolises many normally prescribed drugs. It is encoded by CYP2C19 cistron that is extremely polymorphous, which give rise to different phenotypes that respond otherwise toward drug therapy, and consequence in inauspicious drug reactions such as drug opposition and toxicity.

As of twelvemonth 2008, inauspicious drug reactions were the 5th taking cause of decease in the United States. 7 % of hospitalization instances were due to inauspicious drug reactions, and the frequence increased among the aged up to 30 % . [ 1 ]

Increased cognition in CYP2C19 polymorphism and its clinical impact helps to get the better of inauspicious drug reactions through execution of effectual drug therapy and decrease of drug toxicity.

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Literature Review

2.1 Cytochrome P450 ( CYP )

CYP cistrons are located on the long arm of chromosome 10 ( 10q24 ) . [ 2 ] As of twelvemonth 2006, 115 human CYP cistrons were discovered, with 57 being functional cistrons, and 58 being pseudogenes. [ 3 ] Functional CYP cistrons encode for CYP enzymes, which are found chiefly in the microsomes of hepatocytes.

CYP enzymes are phase I metabolism enzymes, which make endogenous and exogenic compounds more hydrophilic to be eliminated by the kidneys. Examples of endogenous compounds are steroid endocrines and prostaglandins ; illustrations of exogenic compounds are drugs, toxins and carcinogens. [ 4 ]

There are two categories of CYP enzymes. Class I CYP enzymes such as CYP1A1, CYP1A2, CYP2E1 and CYP3A4 do non hold functional polymorphism, and metabolises procarcinogens and drugs. Class II CYP enzymes such as CYP2A6, CYP2B6, CYP2C9, CYP2C19 and CYP2D6 are encoded by extremely polymorphous cistrons, and metabolises drugs but non procarcinogens. [ 1 ]

CYP enzyme system consists of a heme sphere and an NADPH-P450 reductase. [ 5 ] The mechanism of CYP enzymatic action begins when substrate binds to haem Fe ( III ) at the active site. First, reductase transportations an negatron from NADPH to cut down Fe ( III ) . Second, molecular O binds to the reduced Fe ( II ) . Third, protons ( derived from NADPH ) split the molecular O to bring forth a individual O atom, which is added to substrate. [ 6 ]

The current terminology system uses CYP, followed by a figure ( household ) , so a missive ( subfamily ) , and another figure ( protein ) . For case, CYP2C19 is the 19th protein in household 2, subfamily C. [ 3 ] As of twelvemonth 2008, 18 households and 57 subfamilies of human CYP enzymes are identified and grouped based on familial sequence similarity. [ 7 ]

2.2 Cytochrome P450, Family 2, Subfamily C, Polypeptide 19 ( CYP2C19 )

CYP2C19 is a extremely polymorphous cistron located within a bunch of CYP cistrons on chromosome 10q24. [ 8 ]

Polymorphism is defined as familial fluctuation that occurs in at least 1 % of human population. In CYP2C19 cistron, single-nucleotide polymorphisms ( SNPs ) occur in which one base base brace replaces another, ensuing in two types of allelomorphs viz. wild type and discrepancy ( inactive or increased activity ) alleles that are shown in Table 1. [ 9 ]

CYP2C19 cistron encodes for CYP2C19 enzyme, which is present chiefly in the liver. [ 3 ] CYP2C19 enzyme metabolises and activates many normally prescribed drugs and prodrugs, [ 10 ] though it merely plays a minor function in metabolisation of endogenous substrates. [ 11 ] The common substrates ( or drugs ) of CYP2C19 enzyme is shown in Table 4.

SNPs of CYP2C19 cistron alter the map or sum of enzyme, which affects the metabolisation and activation of drugs and prodrugs, therefore predisposes patients to inauspicious drug reactions such as drug opposition and toxicity. [ 9 ]

2.2.1 CYP2C19 Alleles

Table 1 shows the allelomorphs of CYP2C19 cistron and their enzymatic activities. Among the inactive allelomorphs, CYP2C19*2 and CYP2C19*3 are more common in the population, while CYP2C19*4 to CYP2C19*8 are less common. [ 10 ]

Table 1: CYP2C19 allelomorphs and their enzymatic activities.

CYP2C19 allelomorph

Enzymatic activity

*1

Normal ( Wild type )

*2

Inactive

*3

Inactive

*4

Inactive

*5

Inactive

*6

Inactive

*7

Inactive

*8

Inactive

*17

Increased

[ 10 ] Beginning: Genelex. hypertext transfer protocol: //genelex.com/2C19tech.pdf ( accessed 31 August 2012 ) .

SNPs in the coding part of CYP2C19 cistron include deviant splicing site which consequences in CYP2C19*2, and premature halt codon which consequences in CYP2C19*3. CYP2C19*2 encodes a faulty enzyme that catalyses drug molecules at an alternate site alternatively of the active site, while CYP3C19*3 encodes a faulty enzyme with abnormally short polypeptide concatenation. [ 9 ]

CYP2C19*17 is a consequence of SNP that occurs in the 5′-flanking part of CYP2C19 cistron, which leads to increased cistron written text, increased enzyme interlingual rendition and increased metabolic activity. [ 12 ]

Table 2 shows assorted genotypes that give rise to their several phenotypes, and the metabolic activities of these phenotypes.

Table 2: CYP2C19 genotypes, phenotypes and their metabolic activities.

Phenotype

Extensive metaboliser

( EM )

Intermediate metaboliser

( IM )

Poor metaboliser

( PM )

Rapid

metaboliser

( RM )

Genotype

2 wild type allelomorphs

1 active allelomorph

1 inactive allelomorph

2 inactive allelomorphs

1 or 2 increased activity allelomorphs

Metabolic activity

Normal

Reduced

Increased

[ 10 ] Beginning: Genelex. hypertext transfer protocol: //genelex.com/2C19tech.pdf ( accessed 31 August 2012 ) .

Table 3 shows the prevalence of CYP2C19 polymorphism in assorted ethnicities. Although EM phenotype ( given by two wild type allelomorphs ) is non stated in Table 3, it is the most common phenotype in all ethnicities. [ 9 ]

Table 3: Prevalence of CYP2C19 polymorphism in assorted ethnicities.

Phenotype

Prevalence ( % )

Poor metaboliser

( PM )

13 – 19 % in Asiatic population

10 – 20 % in African population

2 – 6 % in Caucasic population

Intermediate metaboliser

( IM )

24 % – 36 % in U.S. population

Rapid metaboliser

( RM )

Approximately 5 % in U.S. population

[ 13 ] Beginning: Desta et Al, Clinical Pharmacokinetics 2002.

2.2.2 Common Substrates of CYP2C19

Table 4 shows the common substrates of CYP2C19 enzyme.

Table 4: Common substrates of CYP2C19.

Drug categories

Examples

Anticonvulsant

Mephenytoin

Diphenylhydantoin

Proton pump inhibitor

( PIP )

Lansoprazole

Omeprazole

Pantaprazole

Rabeprazole

Antidepressant

Diazepam

Imipramine

Prodrug

Clopidogrel ( anti-platelet drug )

Cyclophosphamide ( anti-cancer drug )

Leflunomide ( dainties rheumatoid arthritis )

Proguanil ( anti-malarial drug )

[ 10 ] Beginning: Genelex. hypertext transfer protocol: //genelex.com/2C19tech.pdf ( accessed 31 August 20 )

2.3 Clinical impact of CYP2C19 Polymorphism

Curative Failure of Clopidogrel

Clopidogrel and low-dose acetylsalicylic acid are prescribed as a combination anti-platelet therapy to forestall perennial cardiovascular events in bing patients. [ 14 ]

Clopidogrel is a prodrug that requires activation by CYP2C19 enzyme to organize an active metabolite. The active metabolite inhibits platelet collection and prevents blood coagulum formation, hence reduces the hazard of perennial cardiovascular events. [ 15 ]

IMs and PMs have reduced clopidogrel activation, hence they are exposed to less active metabolite, which consequences in less thrombocyte suppression and higher hazard of perennial cardiovascular events.

A research conducted by Mega et Al, 2009 showed that in comparing to EMs, the plasma concentration of active metabolite in IMs and PMs was 32.4 % lower, and the thrombocyte collection clip in IMs and PMs reduced by 9 % bespeaking there was less platelet suppression. As a consequence, the hazard of perennial cardiovascular events ( myocardial infaction or shot ) increased by 53 % , and the hazard of stent thrombosis increased by a factor of 3. [ 16 ]

However, since IMs and PMs have less platelet suppression, they have lower hazard of shed blooding. [ 17 ]

Helicobacter pylori ( H. pylori ) obliteration

H. pylori infection is treated with ternary therapy as first-line regimen, and quadruplicate therapy as second-line regimen. Both ternary and quadruplicate therapies consist of a proton pump inhibitor ( PIP ) and two types of antibiotics. An add-on, Bi is prescribed for quadruplicate therapy. [ 18 ]

PPI map by suppressing acerb production in tummy in order to make a less acidic intragastric pH. Antibiotics against H. pylori have greater stableness and bioavailability under a less acidic status, which increases the obliteration rate of H. pylori. [ 19 ]

PPI ( such as Prevacid, Prilosec or rabeprazole ) is metabolised by CYP2C19 enzyme. IMs and PMs have reduced PPI metamorphosis that prolongs the half life of PPI, which consequences in higher H. pylori obliteration rate.

A research conducted by Schwab et Al, 2004 showed that serum degree of Prevacid and H. pylori obliteration rate were correlated. They were highest in PMs ( 753 ng/ml and 100 % ) , intermediate in IMs ( 59 ng/ml and 97.8 % ) and lowest in EMs ( 21 ng/ml and 21 % ) . [ 20 ]

In order to increase H. pylori obliteration rate in EMs, physicians can either increase PIP dose, or prescribe rabeprazole. A research conducted by Kuo et Al, 2010 showed that use of rabeprazole in second-line regimen consequences in higher H. pylori obliteration rate among EMs. [ 21 ]

2.3.3 Toxicity

CYP2C19 enzyme is involved in drug metamorphosis and riddance. In IMs and PMs, both metabolic and elimination rate of drugs are reduced, doing them prone to toxicity. Table 5 shows the metabolic and riddance rate of drugs in IMs and PMs. Table 6 shows the types of toxicity caused by certain drugs.

Table 5: Metabolic and riddance rate of drugs in IMs and PMs.

Drugs

Metabolic / Elimination rate in IMs and PMs

Nelfinavir

( anti-retroviral drug )

Metabolic rate reduced by 50 % [ 22 ]

Indisulam

( anti-cancer drug )

Elimination rate reduced by 50 % [ 23 ]

Voriconazole

( anti-fungal drug )

Elimination rate reduced by 49 % [ 24 ]

Beginnings:

[ 22 ] Hirt et Al, British Journal of Clinical Pharmacology 2008.

[ 23 ] Anthe et Al, Clinical Cancer Research 2007.

[ 24 ] Weiss et Al, The Journal of Clinical Pharmacology 2009.

Table 6: Types of toxicity caused by certain drugs.

Drugs

Types of toxicity

Diphenylhydantoin

( antiepileptic )

Neurological toxicity [ 25 ]

Indisulam

( anti-cancer drug )

Hematologic toxicity [ 23 ]

Cyclophosphamide

( anti-cancer drug )

Ovarian toxicity [ 26 ]

Leflunomide

( dainties rheumatoid arthritis )

Hepatoxicity [ 27 ]

Beginnings:

[ 23 ] Anthe et Al, Clinical Cancer Research 2007.

[ 25 ] Dorado et Al, The Pharmacogenomics Journal 2012.

[ 26 ] Singh et Al, The Journal of Rheumatology 2007.

[ 27 ] Wiese et Al, Arthritis Research and Therapy 2012.

Ethical Issues

First, research workers must obtain informed consent from human topics who participate in clinical surveies. The hazards associated with surveies must be disclosed, as topics frequently suffer from serious medical complications such as drug toxicity, myocardial infarction, shot, and stent thrombosis.

Second, research establishments should supply proper medical attention for topics who suffer from medical complications.

Research Plan

Researchs on find of more clinically of import CYP2C19 allelomorphs, solutions to get the better of drug opposition and toxicity caused by CYP2C19 polymorphism, and alternate interventions that are non affected by CYP2C19 polymorphism should be conducted. [ 28 ]

In add-on, a more low-cost CYP2C29 genotyping check should be discovered so that intervention regimen can be personalised to increase success rate.

Decision

CYP2C19 polymorphism affects the metabolisation of drugs and activation of prodrugs, which leads to drug opposition and toxicity. Drug dose version is the current solution to get the better of this job. In future, drugs that are non affected by CYP2C19 polymorphism should be discovered, so that they can be administered in all ethnicities with better curative results.