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Lecture 3

PHAR2210 Lecture Notes - Lecture 3: Partition Coefficient, Active Metabolite, Lipophilicity


Department
Pharmacology
Course Code
PHAR2210
Professor
Ricky Chen
Lecture
3

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Drug Metabolism:
Drugs can interfere with other drugs
Genetic background can influence ability to metabolise drugs
DME are essential catalyst
-
active site (metabolite a drug)
OH= makes the drug more polar and more water soluble
Need to protect the body against foreign molecules
DME
-
Definition: the chemical alteration (ie structural modification) of drugs and foreign chemicals ("xenobiotics")
by drug
-
metabolising enzymes (DME) in the body
**OH metabolites are more polar, more water soluble and therefore facilitates the excretion from the body
Drug metabolism usually generates multiple metabolites from a single "parent" drug
Eg: chlorpromazine forms >100 metabolites in humans
Many form at very low levels
The number of metabolites formed varies from drug to drug and species to species (eg: rat vs
human)
Common for drugs to form 8
-
12 metabolites
The metabolite amount varies between molecules
The same drug can metabolise different metabolites
Metabolites:
Oxidative metabolism: usually catalysed by CYP450 and adds
-
OH
1.
sets up the metabolite for further conjugative metabolism via UGT (highly water soluble metabolite)
2.
OR if the drug already has an
-
OH group it can immediately enter the conjugative metabolism
***this can form 2 different metabolites (as shown in the image above)
Foreign molecules made more polar & water
-
soluble (decreases logP)
If the drug is taken repeatedly
-
the body acts like a sponge, always
accumulating lipophilic substances
The need to convert the lipophilic substances into hydrophilic
substances via oxygenation to be excreted via urine
Offsets tendency for lipophilic chemicals to accumulate in body
Kidneys usually remove water
-
soluble metabolites (sometimes bile)
Facilitates excretion from body
Usually increases molecular mass and size of foreign molecules
Metabolism usually decreases the half
-
life (e.g. blood or plasma T of drugs
Protection against lipophilic substances
Possibility of accumulation is decreased
T half is the time for levels to fall by 50% , therefore it is required to take
repeated and regular dosages of a drug as metabolism is a clearance of the
drug in the blood and decreases the therapeutic response
When the drug is administered, the blood conc increases to the Cmax
The blood conc. then falls as the drug metabolises in various tissues
Consequences of Metabolism 1:
When a drug undergoes chemical modification
-
no longer binds to its target receptor and therefore decreases
the pharmacological response
Metabolite has less affinity for receptor (poor 'fit" and lower logP)
By changing drug structure, metabolism often reduces biological activity
Consequences of Metabolism 2:
Cmax
6/3/2019
Sunday, 3 March 2019 9:05 PM
Lecture Page 1

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Metabolite has less affinity for receptor (poor 'fit" and lower logP)
i.e. "active metabolites"
contribute to the pharmacology of parent drug
Active metabolites can sometimes be used rather than the parent drug
However, some metabolites retain pharmacological activity
e.g. Nortriptyline [antidepressant]
metabolite of Amitriptyline
Active metabolites have been marketed as drugs in own right
Inactive metabolites are more common
So structurally different to parent compound and therefore lose infinity
-
therefore repeated doses are
required as inactive metabolites are always form therefore no pharmacological response
A drug that is inactive until it is metabolised is a
"pro
-
drug"
"first-pass clearance"
A lot of enzymes that metabolise are found in the gut and epithelium and liver
As drugs make their way to liver they're significantly metabolised before it reaches the
systemic circulation (reducing the active drug administed)
Attempt to maximise the oral availability of drugs
Mostly occurs in liver + gut wall (i.e. chemicals absorbed from Gl-tract are processed before
reaching other tissues
DMEs may also be expressed in extra- hepatic tissues (e.g. gut wall, kidney, lung, etc)
The DMEs involved are mainly located in smooth endoplasmic reticulum of liver (some are also
cytosolic)
Some DMEs may also metabolise endogenous molecules such as hormones
General Features of Xenobiotic Metabolism:
>57 CYP genes in human genome
Iron-containing proteins (contain Fe atom in haem group)
1,2,3 are the most important in xenobiotic (any chemical that enters the body from a foreign
source)
Requires NADPH (cofactors) and oxygen (O2) to metabolise xenobiotic substrate (SH)
Cytochrome P450 (CYP450)
Lecture Page 2
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