drug metabolism Flashcards
why is drug metabolism important in pharmacokinetics
- optimises pharmacokinetics and safety profiles of drug candies in drug discovery and development
- most metabolic products are less pharmacologically active except - prodrugs such as ethrytrhomyocin
such as acetaminophen where metabolite could be toxic
such as aflatoxin b1 which is prominent contributor to human liver cancer
what is phase 1 of drug metabolism
bioactivation or detoxification of the compound by oxidation, reduction or hydrolysis
- phase 2 - conjugation reactions to pharmacologically inactivate the impound making it more water soluble for exertion by couplings the drug to endogenous substrates such as glucuronic acid
what are tye sites -of metabolism
- drug administration
- interact and are absorbed by endocytes of gut
- pass through the blood stream via the hepatic portal route
- are metabolised by the liver cytochrome P450 families
- are made bioavilable through the hepatic artery
- are modified and eliminated by the kidney
- reach the target organ
whta actually happens in phase 1
convert the parent compound into more polar metabolite by adding or unmasking functional groups such as oh, sh, nh2, cooh
oxidation is carried out by a group og monooxygenasees in the live
the two types of oxidation reaction are
- oxygen is incorporated into the drug molecule- hydroxylation
- oxidation causes loss of part of drug molecule - de alkylation
what are the 3 different ways paracetomol is metabolised
- most common it undergoes GLUCURONIDATION and is excreted in the urine
- second most common - undergoes SULFATION excreted by the urine
- least common it passes through the cytochrome p-450 pathway producing potentially hepatoxic metabolite NAPQI
in normal doses when this NAPQI is produced it attaches to an antioxidant and is excreted through the liver
however in higher doses it will saturate the glutathione system and forms covelent bonds with proteins in the over which results in hepatoxicity and liver failure
cytochrome p450 enzyme
- this is a major catalyst in most drugs and endogenous compounds in the liver kidney and gi tract, since and lungs
- they have an absorption peak at 450nm in the reduced state when carbon monoxide is present
- majority are located in the smooth endoplasmic reticulum some in the mitochondria, cytostol and lysosomes
- these cells are also called MFOs to define their chemical structure, to form catalytic reaction s these enzymes require a reducing against NADPH to produce water
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CYP450 isoenzymes
- cyp450 have a fm ailey of isoenzymes involved in biotransformation of drugs via oxidation including more than 30 subtypes
- they are membrane proteins located on the smooth endoplasmic reticulum of many tissues which causes difference in the ability of individuals to metabolise drugs
whta occurs in phase 2
types of phase 2 interactions are
- sulphate
- amino acid
- acetylation and methylation
- glucuronid
for orally administrated compounds the steps for metabolism is
1. first pass effect
2. intestinal metabolism
3. liver metabolism
4. enterohepatic recycling
5. gut micro organisms - glucuronidases
the liver is the main site for drug metabolism but it can alos occur in the kidneys, gut, lungs and skin
glucuronide conjugation.
this is the largest and most important pathway of phase 2 metabolism
it requires the UGT enzyme the enzyme system is closes located to the cyp450 on the endoplasmic reticulum
drugs which have hydroxyl or carboxylic acid groups ae easily conjugated with glucoric acid
UGT isoforms - there are so far,i lies of UGT1 and UGT2
the main sights are the liver and epithelial cells of the gi tract
UGTA1 - these are hepatic enzymes utilise a wide range of drugs
the inhibition of metabolism
- competoveley inhibis the metabolism of another drug when sharing similar enzymes or co factors with that drug
- a drug may inhibit one isoenzyme while astcing as substrate for another isoenzyme - quinidine is metabolised by CYP3A4 and inhibits CYP2D6
inhibition of drug metabolism is dependant on the drug dosage
it may also induce blood flow which will limit metabolism
- propanolol reduces the rate of lignocaine metabolism by decreasing hepatic blood flow
how is metabolism controlled
- upregulation and down regulation of CYP450 and UGT isoforms may alter drug metabolism
whta is diffrent about isonaizid
this is used to treat turberculosis
it undergoes phase 2 first then phase 1
isoniazid acid —-> n- acetyl conjugate ———> isonicotinic
hepatotoxic metabolism due to the inability of body to acetylate and remove from tge blood
what are the 3 possible end results of drug metabolism
- drug converted from pharmacologically active to an inactive compound -majority
- conversion og drug metabolite = pjatmocoligally active
- coberson of pharamacologically inactive compound to an active compound - this happens with PRODRUGS
what is the advantages of taking prodrugs
drug is inactive before metabolism
drug becomes active after metabolism
- drug takes affect directly
what are the factor affecting g metobilm
- genetics - about 5 percentage of people have an inactive CYP2D6 - which leads to a loss of analgesics efficacy
- age - CYP activity is 30 to 50 percentage less in infants up to the age of 2-6 months - this causes a difficulty in dosing. and drug metabolism decreases as old age which less nadph which affects metabolism
liver blood flow is 40- 60 percentage reduced, decline in renal clearance - gender - menstrual steriod ,eat abolish causes examples to handle drugs differently, phases of metabolism is responsible for biotransfromation of female steriod hormones, drugs which alter enzymes in phases of metabolism are likely to cause adverse drug reaction in females than males
- disease
- diet - eating things such as antioxidants and polyphenols ( in fruits) polyphenols alter enzymes in phase 1 and 2 reactions
vegetables such as broccoli, brussels sprouted and cauliflower induce CYP1A2 (converts aromatic amines into carcinogens) and GST (involved in decreasing cancers of the gut) - environment
