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METABOLISM OF DRUGS

BIOTRANSFORMATION

PURPOSE
Major Purpose:
- Make the drug inactiveless toxic
- Remove it out of the body
How it is achieved?
- Phase 1 metabolism: inactivate.less souble.
- Phase 2: least soluble in lipid.excretable
How reducing lipid solubility helps in excretion?
- Glomerular filtration, tubular reabsorption
lipid soluble drugs diffuse back to blood
across tubular epithelium. Water soluble can
not!

What exactly happens in phase 1 &


2?

Phase 1.chemical modification


- Oxidation
- Reduction
- Hydrolysis
Phase 2.conjugation with a polar group makes it
less lipid soluble
- Glucuronide conjugation
- Glycine conjugation
- Glutathione conjugation
- Acetylation
- Methylation
- Sulfation

What is first pass


metabolism?

The amount of drug metabolised in its


first passage from site of
administration to circulation
What is the importance of first pass
metabolism?
The amount of first pass metabolism
determines the bioavailability of drug.
Nitoglycerin has extensive first pass
metabolism and it can be avoided by
giving sublingually.
Lignocaine has extensive first pass

First pass contd

Morphine high first passusually


given parenterally.
Propranolol high first pass in liver.
CCF blood supply to liver
reduced.metabolism lessmore
concentration..same with liver
disease.reduce dose.
Peptides inactivated by proteolysis in
git. Parenterally.

prodrug
Inactive themselvesbecome active after
undergoing metabolism.
LDOPA
- Designed with a purpose in mind.
- DopamineparkinsonismBBB
- LDOPA crosses BBB. Converted to dopamine.
Esters..hydrolysisparent drug
Bacampicillin, talampicillinto ampicillin
Better absorbed better bioavailabilitylesser
frequency.better patient compliance
Lesser GI adverse effectssuper infection,
diarrhoea

Prodrug.

Metronidazole Benzoylate.
Metronidazole base is unpalatable.
Paediatric patientpoor acceptance.
Benzoylate is taste lessester..
Erthromycin base bitter ..esters
bland
Mandelamine (methenamine
mandelate).formaldehyde.acidic
pHrenal tubulesformalin itself
fixes cells! Urinary infectionurinary
antiseptic.

Synthetic reactions (Phase 2)


(conjugation)
Non synthetic reactions (phase 1)
Type of reaction Determined by functional group
Determined by
functional group
Limited number
Wide variety
Relatively predictable
Relatively unpredictable
Metabolite
Almost always less lipid-soluble Usually less lipidsoluble
Almost always pharmacologically
inactive
May have less, equal, greater or
different activity
Reactions catalyzed by
Non microsomal enzymes
All except glucuronide
conjugation
Most hydrolyses; some
oxidations and reductions
No stimulation of rate of
biotransformation by other drugs No stimulation of rate of
biotransformation by other drugs
Reactions catalyzed by
microsomal enzymes
Only glucuronide conjugation
Most oxidations and
reductions;
Some hydrolyses
Rate of reaction stimulated by

Cyp450? superfamily

P450s are highly abundant in liver cells.


Reddish brown.heme; hemoproteins
Mcicrosomes ( vesicles)
Endoplasmic reticulum.
Separate out at a centrifuge speed of 100000g.
CYP is a diverse group ofenzymesthat
catalyze theoxidationoforganic
substances.
substratesincludemetabolicintermediates
such aslipids andsteroidalhormones, as
well asxenobiotic substances such as drugs and
othertoxic chemicals.
account 75% metabolic reactions.

Cyp450? Superfamily.
P450 =spectrophotometricpeak at the
wavelength of the absorption maximum
of the enzyme (450nm) when it is in the
reduced state and complexed withCO.
Based on the nature of the electron transfer
proteins CYPs can be classified into several
groups
- Microsomal P450 systems
- Mitochondrial P450 systems
- Bacterial P450 systems
- P450 onlysystems; CYP5(thromboxane
synthase),CYP8(prostacyclin synthase),
and CYP74A (allene oxide synthase).

Nomenclature
Genesencoding CYP enzymes, and the
enzymes themselves, are designated with the
abbreviationCYP followed by a number
indicating the gene family, a capital letter
indicating the subfamily, and another numeral
for the individual gene.
Italicise the name when referring to the gene.
Cyp 3A4 = enzyme
Cyp 3A4 = gene
3 = gene family, A= subfamily, 4 =
individual gene
TheHuman Genome Projecthas identified 57
humangenescoding for the various
cytochrome P450 enzymes.

CYP..

The most common reaction catalyzed


by cytochromes P450 is
amonooxygenase reaction, e.g.,
insertion of one atom of oxygen
into an organic substrate (RH) while
the other oxygen atom isreducedto
water:
RH + O2+ NADPH + H+ ROH +
H2O + NADP+
CYP Enzyme inducers
CYP Enzyme inhibitors
DRUG INTERACTIONS affect

Various enzymes involved in


metabolism of drugs

Examples of Substrates, Inhibitors and


Inducers of CYPs

Enzyme inducers

Phenobarbitone
Phenytoin
Carbamazepine
Rifampicin
Alcohol
Tobacco smoke
Marijuana smoke
Onset 2 days, peak 2-3 weeks,
increase in smooth endoplasmic
reticulum

Rifampicin
Auto induction
Warfarin
Oral contraceptives
Phenobarbitone
Warfarin .stabilised on phenobarb,
if phenobarb withdrawn, fatal
hemorrhage.
- Oral contraceptives

Enzyme induction.

Phenytoin
Warfarin
Theophylline
Carbamazepine
Auto induction
Warfarin
But inhibits phenytoin metabolism
Smoking
Theophylline
Imipramine
Pentazocin
propranolol

Enzyme induction.

ETHANOL
- Chronic alcoholism, liver disease,
abnormal drug metabolism
- Acute ethanol administration
inhibit competition
Inhibit NADPH cytochrome P-450
reductase, the rate limiting step in
the oxidative biotransformation of
drugs; higher plasma levels of many
benzodiazepines;
also inhibit phase two reactions.

Enzyme induction.

chronic ethanol intake enhances the rate of


drug metabolism; increase in microsomal mass.
- Phenytoin
- Phenobarbitone
- Warfarin
Withdrawal of alcohol may cause drug
interaction.
Food:
a low protein diet, diminished NADPH
dependent enzymes.
High carb dietlow microsomal MFO
activity.

Enzyme induction.

Crigler-Najjar syndrome type II and


Gilbert's syndrome; unconjugated
hyperbilirubinemia; reduction in the
activity of glucuronyl transferase;
jaundice; phenobarbitone; increased
glucuronyl tranferase, incresed blood
flow, increased bile flow.
Phenobarbitone, phenytoin; long
term; epilepsy; increased vit D
inactivation, osteomalacia,